TW202132313A - Imidazolidinone compound, preparation method therefor and use thereof - Google Patents

Abstract

An imidazolidinone compound represented by formula (I), or a stereoisomer thereof, a geometric isomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, a synthesis method therefor, and use thereof.

Description

Imidazolidinone compounds, pharmaceutical compositions containing them, and applications thereof

The present invention relates to an imidazolidinone compound, which plays a role in regulating cell proliferation, apoptosis, migration, angiogenesis and other processes. The present invention also relates to pharmaceutical compositions containing such inhibitors and their application in the treatment of PI3K-mediated diseases.

The PI3K signaling pathway is a key signaling pathway that controls growth, proliferation, survival, differentiation, metastasis, and apoptosis in cells. Because PI3K, Akt and mTOR are the key sites on this pathway, they are called PI3K/Akt/mTOR signaling pathway. In recent years, PI3K inhibitors have become a research hotspot of anti-tumor drugs at home and abroad.

PI3K is activated by RTK or Ras to catalyze phosphoinositide-3,4-diphosphate (PIP2) to phosphoinositol-3,4,5-triphosphate (PIP3). PIP3 binds to protein kinases such as Akt and 3-phosphoinositide (PIP)-dependent protein kinase (PDK), activates Akt by phosphorylation, and transfers Akt from the cytoplasm to the nucleus. After activation, Akt can further phosphorylate downstream effector substrates to affect cell survival, cell cycle, growth and other cell activities (Ma K, Cheung SM, Marshall AJ, etc., Cell Signal, 2008, 20:684-694). Therefore, The PI3K/Akt/mTOR signaling pathway can inhibit cell apoptosis, enhance cell tolerance, promote cell survival and proliferation, participate in angiogenesis, and promote tumor growth and metastasis.

Phosphoinositide 3-kinase (PI3K) belongs to the Lipid kinase family. The members of this family are divided into three types: type I, type II and type III according to the activation mechanism and structural characteristics of PI3K (Vanhaesebroeck B, Waterfield MD ; Exp Cell Res, 1999, 253:239-254). At present, the more thorough research is type I PI3K. According to the different types of cell surface receptors, type I PI3K is further divided into two different subtypes, IA and IB. These two subtypes are derived from tyrosine protein kinase receptors (RTKs) and G protein-coupled receptors. (GPCRs) accept transmission signals (Wu P, Liu T, Hu Y; Curr Med Chem, 2009, 16:916-930). Class IA PI3K contains three subtypes: PI3Kα, PI3Kβ, and PI3Kδ. Class IB PI3K contains only one subtype of PI3Kγ. Type II PI3K kinases are divided into three subtypes: PI3KC2α, PI3KC2β, and PI3KC2γ according to their C-terminal structure. However, their substrates in the body are not yet clear, and the understanding of their mechanism of action and specific functions is relatively limited (Falasca M, T. Muffucci; Biochem Soc Trans, 2007, 35:211-214). Type III PI3K kinase has only one member, Vps34 (Vacuolar Protein Sorting 34), which acts as a calibration at the protein level when regulating the downstream mTOR signal cascade (Schu P, Takegawa. K, Fry. M et al., Science, 1993, 260:88-91).

Among the four subtypes of type I PI3K, PI3Kα and PI3Kβ are expressed in various organs, while PI3Kδ and PI3Kγ are mainly distributed in bone marrow cells (Kong D, Yamori T; Cancer Sci, 2008, 99:1734-1740). Among them, PI3Kα is most closely related to the occurrence and development of tumors. The gene encoding PI3Kα catalytic subunit p110α is PIK3CA, and its mutations are common in various malignant tumors, including breast cancer, colon cancer, endometrial cancer, gastric cancer, and ovarian cancer. Cancer and lung cancer (Steelman. LS, Chappell. WH, Abrams. SL, etc., Aging, 2011, 3:192-222). The abnormal activation of PI3Kα will up-regulate and activate the PI3K signaling pathway, promote excessive cell proliferation, growth and metastasis, leading to the formation of tumors. The other three subtypes PI3Kβ, PI3Kδ, and PI3Kγ, although they play a role in thrombosis, immune function, allergic and inflammatory response, respectively, but by affecting the catalytic activity, physicochemical properties, interaction and recognition, etc., they play a role in the occurrence of tumors. It also plays an important role.

The PI3K inhibitors that have been studied more in the early stage are wortmannin and LY294002, both of which play an important role in studying the physiological functions of PI3K and the mechanism of signaling pathways, and provide an important basis for subsequent research. , Known as the first generation PI3K inhibitor. Through the research on wortmannin and LY294002, the second generation PI3K inhibitors with newer structure, higher activity and better pharmacokinetic properties have been developed, including morpholinoaryls, imidazopyridines and imidazo Quinolines, etc., have brought new hope to tumor treatment. Among them, dozens of PI3K inhibitors are in the clinical research stage, which are mainly divided into pan-PI3K inhibitors, PI3K/mTOR dual inhibitors and PI3K subtype specific inhibitors.

Alpelisib (BYL719) is the first PI3Kα selective inhibitor developed by Norvartis, and its inhibitory activity on p110α is 5 nM. Preclinical data show that BYL719 can inhibit the phosphorylation of Akt, block the PI3K signaling pathway and inhibit the growth of breast cancer cells containing PIK3CA mutations (Dejan Juric et al., Cancer Res, 2012, 72:1). The compound has been approved for marketing by the U.S. Food and Drug Administration (FDA) on May 24, 2019, for the treatment of patients with PIK3CA gene mutations, HR ⁺ /HER2 ^- advanced or metastatic breast cancer, and receiving endocrine therapy Postmenopausal women and men with disease progression during or after the program. At the same time, previous results show that this PI3Kα-specific small molecule inhibitor ^{has a good prospect in the treatment of diseases such as head and neck cancer, ovarian cancer, triple-negative breast cancer, HER2+} breast cancer, PIK3CA-related overgrowth disease spectrum and so on. If the drug can expand its indications, it will produce huge economic and social benefits.

In order to achieve better tumor treatment effects, better meet market demand, and provide a new drug choice for clinical use, we hope to develop a new generation of PI3K with higher activity, better pharmacokinetics, and lower toxicity. Inhibitor.

The object of the present invention is to provide an imidazolidinone compound as a PI3K inhibitor.

式(Ⅰ) 其中， X選自O或S； R₁ 選自H、CN、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、C_3-6 雜環基、C_6-8 芳基、C_5-8 雜芳基、OR_a 或-NR_a R_b ；所述C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、C_3-6 雜環烷基、C_6-8 芳基和C_5-8 雜芳基可任選地被1個或多個選自鹵素、CN、OR_a 、氧代基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基或C_3-6 雜環基的取代基所取代； R₂ 選自H、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、C_3-6 雜環基、C_6-8 芳基、C_5-8 雜芳基；所述C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_3-6 環烷基、C_3-6 雜環基、C_6-8 芳基和C_5-8 雜芳基可任選地被1個或多個選自鹵素、CN、-OH、-NO₂ 、C_1-6 烷基、C_1-6 鹵代烷基、C_2-6 烯基、C_2-6 鹵代烯基、C_2-6 炔基、C_2-6 鹵代炔基、C_3-6 環烷基、C_3-6 鹵代環烷基、C_3-6 雜環基、C_3-6 鹵代雜環基、C_6-8 芳基、C_6-8 鹵代芳基、C_5-8 雜芳基、C_5-8 鹵代雜芳基、氧代基、-OR_a 、-NR_a R_b 、-C(O)R_a 、-C(O)OR_a 、-C(O)NR_a R_b 、-S(O)R_a 或-S(O)₂ R_a 的取代基所取代； R₃ 選自H、鹵素、CN、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、-OR_a 或-NR_a R_b ；所述C_1-6 烷基、C_2-6 烯基、C_2-6 炔基可任選地被1個或多個選自鹵素、CN、-OR_a 、-NR_a R_b 、-C(O)R_a 、-C(O)OR_a 、-C(O)NR_a R_b 、-S(O)R_a 或-S(O)₂ R_a 的取代基所取代； R₄ 選自H、鹵素、CN、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、氧代基、C_1-6 鹵代烷基、C_2-6 鹵代烯基、C_2-6 鹵代炔基、C_1-6 烷氧基、C_1-6 鹵代烷氧基、-OR_a 、-NR_a R_b 、-C(O)R_a 、-C(O)OR_a 、-C(O)NR_a R_b 、-S(O)R_a 或-S(O)₂ R_a ； R₅ 選自H、鹵素、CN、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵代烷基、C_2-6 鹵代烯基、C_2-6 鹵代炔基、C_1-6 烷氧基、C_1-6 鹵代烷氧基、-OR_a 、-NR_a R_b 、-S(O)R_a 或-S(O)₂ R_a ； R₆ 選自H、鹵素、CN、氧代基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 烷氧基、C_3-6 環烷基、C_3-6 雜環基、C_6-8 芳基、C_5-8 雜芳基、-OR_a 、-NR_a R_b 、-C(O)R_a 、-C(O)O R_a 、-C(O)NR_a R_b 、-S(O)R_a 或-S(O)₂ R_a ；所述C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 烷氧基、C_3-6 環烷基、C_3-6 雜環基、C_6-8 芳基和C_5-8 雜芳基可任選地被1個或多個選自鹵素、CN、氧代基、-NO₂ 、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、-OR_a 、-NR_a R_b 、-C(O)R_a 、-C(O)OR_a 、-C(O)NR_a R_b 、-S(O)R_a 或-S(O)₂ R_a 的基團所取代；或者， 兩個R₆ 與其相連接的C原子共同形成C_3-6 環烷基或C_3-6 雜環基； R_a 和R_b 分別獨立地選自H、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 烷氧基、C_3-6 環烷基、C_3-6 雜環基、C_6-8 芳基、C_5-8 雜芳基；所述C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 烷氧基、C_3-6 環烷基、C_3-6 雜環基、C_6-8 芳基、C_5-8 雜芳基可任選地被鹵素、CN、-OH、-NH₂ 、C_1-6 烷基、C_1-6 烷氧基、C_1-6 鹵代烷基、C_1-6 鹵代烷氧基所取代； m選自0、1、2、3或4； n選自0、1、2或3； y選自0、1、2、3、4、5或6。The present invention first provides the compound represented by formula (I) and its stereoisomers, geometric isomers and tautomers, or pharmaceutically acceptable salts, solvates, chelates, and non-covalent complexes thereof Substances or prodrugs,

Formula (I) wherein X is selected from O or S; R _{1 is} selected from H, CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _6-8 aryl, C _5-8 heteroaryl, OR _a or -NR _a R _b ; the C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _6-8 aryl, and C _5-8 heteroaryl may optionally be selected from halogen, CN, OR _a , oxo group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl or C _3-6 heterocyclic group substituted ; R _{2 is} selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _6-8 aryl , C _5-8 heteroaryl; the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _{6 -8} aryl group and C _5-8 heteroaryl group can be optionally substituted by one or more selected from halogen, CN, -OH, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, C _3-6 heterocyclic group, C _3-6 halogenated heterocyclic group, C _6-8 aryl group, C _6-8 halogenated aryl group, C _5-8 heteroaryl group, C _5-8 halogenated heteroaryl group , Oxo group, -OR _a , -NR _a R _b , -C(O)R _a , -C(O)OR _a , -C(O)NR _a R _b , -S(O)R _{a or-} S(O) ₂ R _a is substituted by a substituent; R _{3 is} selected from H, halogen, CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _a or -NR _a R _b ; The C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group may optionally be selected from halogen, CN, -OR _a , -NR _a R _{b, -C (O) R a} , -C (O) oR a, -C (O) NR a R b, -S (O) R a , or -S (O) ₂ R _a the substituents; R _{4 is} selected from H, halogen, CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, oxo, C _1-6 haloalkyl, C _2-6 haloalkenyl , C _2-6 haloalkynyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -OR _a , -NR _a R _b , -C(O)R _a , -C(O)OR _{a, -C (O) NR a} R b, -S (O) R a , or _{-S (O) 2 R a;} R 5 is selected from H, halo, CN, C _1-6 alkyl, C _2-6 Alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _2-6 haloalkenyl, C _2-6 haloalkynyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -OR _a , -NR _a R _b , -S (O) R _a, or _{-S (O) 2 R a;} R 6 is selected from H, halogen, CN, oxo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _6-8 aryl, C _5-8 heteroaryl, -OR _a , -NR _a R _b , -C(O)R _a , -C(O)OR _a , -C(O)NR _a R _b , -S(O)R _a or -S(O) ₂ R _a ; the C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _6-8 aryl and C _{The 5-8} heteroaryl group can be optionally substituted by one or more selected from halogen, CN, oxo, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , -OR _a , -NR _a R _b , -C(O)R _a , -C(O)OR _a , -C(O)NR _a R _b , -S(O)R _a or -S(O) ₂ R _a group is substituted; or, two R ₆ and the C atom to which they are connected together form a C _3-6 cycloalkyl group or a C _3-6 heterocyclic group; R _a and R _b are each independently selected from H , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _6-8 Aryl, C _5-8 heteroaryl; the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _6-8 aryl, C _5-8 heteroaryl can be optionally substituted by halogen, CN, -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkane Substituted by oxy, C _1-6 haloalkyl, C _1-6 haloalkoxy; m is selected from 0, 1, 2, 3 or 4; n is selected from 0, 1, 2 or 3; y is selected from 0, 1 , 2, 3, 4, 5, or 6.

Regarding the compound represented by formula (I) and its stereoisomers, geometric isomers and tautomers, the present invention further provides some better technical solutions:

In some embodiments, R ₁ is a C _1-6 alkyl group or a C _3-6 cycloalkyl group, and the C _1-6 alkyl group and C _3-6 cycloalkyl group may be independently optionally substituted with halogen.

In some embodiments, R _{2 is} selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _6-8 aryl or C _5-8 heteroaryl; The C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 heterocyclic group, C _6-8 aryl group and C _5-8 heteroaryl group may be optionally substituted by 1 or more halogens, _{-CN, -OH, -NR a R b} , C 1-6 alkyl or C _1-6 haloalkyl groups; said R _a and R _{b are} each independently selected from H or C _1-6 alkyl.

In some embodiments, R _{3 is} selected from H, halogen, CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _2-6 haloalkenyl Or C _2-6 haloalkynyl.

In some embodiments, R _{6 is} selected from H, halogen, CN, -NH ₂ , oxo, -OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkoxy, C _1-6 haloalkyl, C _2-6 haloalkenyl, C _2-6 haloalkynyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _6-8 Aryl or C _5-8 heteroaryl.

式(Ⅱ) 。In some embodiments, the compound represented by formula (I) is further a compound represented by formula (II):

Formula (Ⅱ).

式(Ⅲ-1) 其中，所述R₁ 為C_1-6 烷基或C_1-6 鹵代烷基。In some embodiments, the compound represented by formula (I) is further a compound represented by formula (III-1):

Formula (III-1) wherein, the R ₁ is a C _1-6 alkyl group or a C _1-6 haloalkyl group.

式(Ⅲ-2)。In some embodiments, the compound represented by formula (I) is further a compound represented by formula (III-2):

Formula (Ⅲ-2).

In some embodiments, R _{3 is} selected from H, halogen, C _1-6 alkyl, or C _2-6 alkenyl.

In some embodiments, both R ₄ and R ₅ are H.

式(Ⅳ) 其中： R₁ 為C_1-6 烷基或C_1-6 鹵代烷基； R₂ 選自H、C_1-6 烷基、C_3-6 環烷基、C_3-6 雜環基、C_6-8 芳基或C_5-8 雜芳基；所述C_1-6 烷基、C_3-6 環烷基、C_3-6 雜環基、C_6-8 芳基和C_5-8 雜芳基可任選地被1個或多個鹵素、-CN、-OH、-NR_a R_b 、C_1-6 烷基、C_1-6 鹵代烷基、C_1-6 烷氧基或C_1-6 鹵代烷氧基所取代； R₃ 選自選自H、鹵素、C_1-6 烷基或C_2-6 烯基； R₆ 選自H、鹵素、-NH₂ 、氧代基、-OH、C_1-6 烷基、C_1-6 烷氧基、C_1-6 鹵代烷基、C_1-6 鹵代烷氧基、C_3-6 環烷基或C_6-8 芳基； R_a 和R_b 分別獨立地選自H或C_1-6 烷基； y選自0、1、2、3、4、5或6。In some embodiments, the compound represented by formula (I) is further a compound represented by formula (IV):

Formula (IV) wherein: R ₁ is C _1-6 alkyl or C _1-6 haloalkyl; R _{2 is} selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycle Group, C _6-8 aryl group or C _5-8 heteroaryl group; the C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 heterocyclic group, C _6-8 aryl group and C _{The 5-8} heteroaryl group can be optionally substituted by one or more halogen, -CN, -OH, -NR _a R _b , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy Group or C _1-6 haloalkoxy; R _{3 is} selected from H, halogen, C _1-6 alkyl or C _2-6 alkenyl; R _{6 is} selected from H, halogen, -NH ₂ , oxo , -OH, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl or C _6-8 aryl; R _a and R _b are each independently selected from H or C _1-6 alkyl; y is selected from 0, 1, 2, 3, 4, 5 or 6.

In some embodiments, the X is O.

式(Ⅴ)。In some embodiments, the compound represented by formula (I) is further a compound represented by formula (V):

Formula (Ⅴ).

In some embodiments, R _{2 is} selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C ₆ aryl or C _5-6 heteroaryl; the C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C ₆ aryl and C _5-6 heteroaryl may optionally be substituted by one or more halogens, -CN,- OH, -N-(CH ₃ ) ₂ , C _1-6 alkyl or C _1-6 haloalkyl.

In some embodiments, R _{6 is} selected from H, halogen, -NH ₂ , oxo, -OH, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, or C ₆ aryl. base.

式(Ⅵ) 其中， R₁ 選自C_1-6 烷基或C_1-6 鹵代烷基； R₂ 選自H、C_1-6 烷基、C_3-6 環烷基、C_3-6 雜環基、C₆ 芳基或C_5-6 雜芳基；所述C_1-6 烷基、C_3-6 環烷基、C_3-6 雜環基、C₆ 芳基和C_5-6 雜芳基可任選地被1個或多個鹵素、-CN、-OH、-N-(CH₃ )₂ 、C_1-6 烷基或C_1-6 鹵代烷基所取代。In some embodiments, the compound represented by formula (I) is further a compound represented by formula (VI):

Formula (VI) wherein, R _{1 is} selected from C _1-6 alkyl or C _1-6 haloalkyl; R _{2 is} selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 hetero Cyclic group, C ₆ aryl group or C _5-6 heteroaryl group; the C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 heterocyclic group, C ₆ aryl group and C _5-6 Heteroaryl groups may be optionally substituted with one or more halogens, -CN, -OH, -N-(CH ₃ ) ₂ , C _1-6 alkyl, or C _1-6 haloalkyl.

In some embodiments, R ₁ is C _1-4 alkyl; R _{2 is} selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C ₆ aryl or C _5- C ₆ heteroaryl; said R ₁ and R ₂ may be independently optionally substituted with halogen.

In some embodiments, R _{2 is} selected from C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, phenyl, or halophenyl.

In some embodiments, R _{1 is} selected from -CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -CF ₃ or -CHF ₂ .

式(Ⅶ) 其中，所述R₂ 選自H、C_1-6 烷基、C_3-6 環烷基、C_3-6 雜環基、C₆ 芳基或C_5-6 雜芳基；所述R₂ 任選地經鹵素取代。In some embodiments, the compound represented by formula (I) is further represented by formula (VII):

Formula (VII) wherein, the R _{2 is} selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C ₆ aryl or C _5-6 heteroaryl; The R _{2 is} optionally substituted with halogen.

In some embodiments, R ₁ is C _1-4 alkyl; R _{2 is} selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C ₆ aryl or C _5-6 heteroaryl; said R ₁ and R ₂ may be independently optionally substituted with F.

In some embodiments, R _{2 is} selected from -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CF ₃ , cyclopropyl, cyclobutyl, phenyl, or pyridyl; the- CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CF ₃ , cyclopropyl, cyclobutyl, phenyl, or pyridyl can be optionally substituted with halogen.

In some embodiments, the halogen is F.

In some embodiments, R _{2 is} selected from -CH ₃ , -CH(CH ₃ ) ₂ , cyclopropyl, phenyl, or halogen-substituted phenyl.

In some embodiments, R ₁ is -CH(CH ₃ ) ₂ .

In some embodiments, R ₁ is -CHF ₂ .

In some embodiments, R _{2 is} selected from -CH ₃ , -CH(CH ₃ ) ₂ , cyclopropyl, phenyl, or F-substituted phenyl, pyridyl, or F-substituted pyridyl.

In some embodiments, R _{2 is} selected from -CH ₃ , -CH(CH ₃ ) ₂ , cyclopropyl, phenyl, or F-substituted phenyl.

In some embodiments, R ₂ is -CH(CH ₃ ) ₂ or cyclopropyl.

式(Ⅷ)。In some embodiments, the compound represented by formula (I) is further represented by formula (VIII):

Formula (Ⅷ).

The present invention further provides some particularly good technical solutions regarding the compounds represented by formula (I) and their stereoisomers, geometric isomers and tautomers, and the compounds refer to: 1) (2S)-1-(2-(5-isopropyl-3-methyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f]imidazole And [1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-methanamide; 2) (2S)-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f] Imidazole [1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-carboxamide; 3) (2S)-1-(2-(5-isopropyl-2,4-dioxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-yl)-5, 6-Dihydrobenzo[f]imidazole[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 4) (2S)-1-(2-(3-(4-Fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzene And [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 5) (2S)-1-(2-(5-cyclopropyl-3-methyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole And [1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-methanamide; 6) (2S)-1-(2-(3-cyclobutyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f] Imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 7) (2S)-1-(2-(3-ethyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole And [1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-methanamide; 8) (2S)-1-(2-(5-Difluoromethyl-3-methyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f] Imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 9) (2S)-1-(2-(5-isopropyl-2,4-dioxo-3-phenylimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole And [1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-methanamide; 10) (S)-1-(2-((S)-5-isopropyl-2,4-dioxo-3-phenylimidazolidin-1-yl)-5,6-dihydrobenzo [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 11) (S)-1-(2-((R)-5-isopropyl-2,4-dioxo-3-phenylimidazolidin-1-yl)-5,6-dihydrobenzo [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 12) (2S)-1-(2-(5-isopropyl-2,4-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)-5, 6-Dihydrobenzo[f]imidazole[1,2 -d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 13) (2S)-1-(2-(5-isopropyl-2,4-dioxo-3-propylimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole And [1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-methanamide; 14) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f ]Imidazo[1,2-d] [1,4]oxazepine-9-yl)-2-methylpyrrolidin-2-methamide; 15) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f ]Imidazo[1,2-d] [1,4]thiazolin-9-yl)-4,4-difluoropyrrolidine-2-methamide; 16) (2S)-1-(2-(5-isopropyl-3-(1-methyl-1H-1,2,4-triazol-5-yl)-2,4-dioxoimidazole Alkyl-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 17) (2S,4S)-4-amino-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-di Hydrobenzo[f]imidazole[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 18) (2S)-1-(2-(3-(2-Fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzene And [f]imidazole[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 19) (2S)-1-(2-(3-(4-chlorophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzene And [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 20) (2S)-4-(tert-butoxy)-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5, 6-Dihydrobenzo[f]imidazole[1,2] -d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 21) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f ]Imidazo[1,2-d] [1,4]oxazepine-9-yl)-4,4-dimethylpyrrolidine-2-methamide; 22) (2S)-1-(2-(3-(2,2-Difluoroethyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6- Dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 23) (2S)-1-(2-(3,5-Diisopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f]imidazo[ 1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-carboxamide; 24) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f ]Imidazo[1,2-d] [1,4]oxazepine-9-yl)-4-phenylpyrrolidine-2-methamide; 25) (2S)-1-(2-(3-(3-chloro5-cyanophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6 -Dihydrobenzo[f]imidazo[1,2 -d] [1,4]thiazolin-9-yl)pyrrolidine-2-carboxamide; 26) (2S)-1-(2-(3,5-Diisopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f]imidazo[ 1,2-d] [1,4]thiazolin-9-yl)pyrrolidine-2-carboxamide; 27) (2S)-1-(2- (3-azetidin-3-yl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6- Dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 28) (2S)-1-(2-(3-Methyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d] [1,4] oxazepine-9-yl)pyrrolidine-2-carboxamide; 29) (2S)-1-(2- (5-tert-butyl-3-methyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole And [1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-carboxamide; 30) (S)-1-(2-((R)-3-(4-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6 -Dihydrobenzo[f]imidazo[1,2]-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 31) (S)-1-(2-((S)-3-(4-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6 -Dihydrobenzo[f]imidazo[1,2] -d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 32) (2S)-1-(2-((5R)-3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzene And [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 33) (2S)-1-(2-((5S)-3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzene And [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 34) (2S)-1-(2-(3-(2-hydroxyethyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzene And [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 35) (2S)-1-(2-(3-(2-Fluoroethyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzene And [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 36) (2S)-1-(2-(3-(2-(dimethylamino)ethyl)-5-)isopropyl-2,4-dioxoimidazolidine-1-yl)-5 ,6-Dihydrobenzo[f]imidazo[1,2- d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 37) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f ]Imidazo[1,2-d] [1,4]thiazolin-9-yl)pyrrolidine-2-carboxamide; 38) (2S)-1-(2-(3-(6-Fluoropyridin-3-yl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6- Dihydrobenzo[f]imidazo[1,2 -d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 39) (2S)-1-(2-(3-(5-fluoropyridin-3-yl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-di Hydrobenzo[f]imidazo[1,2] -d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 40) (2S)-1-(2-(3-(3-cyano-5-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5, 6-Dihydrobenzo[f]imidazo[1,2 -d] [1,4]oxazepine-9-yl)-4-fluoropyrrolidine-2-methamide; 41) (2S)-1-(2-(3-(3-Chloropyrimidin-2-yl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6- Dihydrobenzo[f]imidazo[1,2 -d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 42) (2S)-1-(2-(3-cyclopentyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f] Imidazole [1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-carboxamide; 43) (2S)-1-(2-(3-(cyanomethyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 44) (2S)-1-(2-(5-isopropyl-3-methyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole And [1,2-d] [1,4]thiazolin-9-yl)pyrrolidine-2-methamide; 45) (2S)-1-(2-(3-(2,2-Difluoroethyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6- Dihydrobenzo[f]imidazo[1,2-d] [1,4]thiazolin-9-yl)pyrrolidine-2-carboxamide; 46) (2S)-1-(2-(3-Cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-3-vinyl-5,6-dihydro Benzo[f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 47) (2S)-1-(3-Chloro-2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzene And [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 48) (2S)-1-(2-(3-Cyclopropyl-5-(difluoromethyl)-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo [f]imidazo[1,2-d] [1, 4]thiazolin-9-yl)pyrrolidine-2-carboxamide; 49) (2S,3S)-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[ f]imidazo[1,2-d][1,4]oxazepine-9-yl)-3-hydroxypyrrolidine-2-methamide; 50) (2S)-1-(2-(3-Cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-3-methyl-5,6-dihydro Benzo[f]imidazo[1,2-d] [1,4]oxazepine-9-yl)-4-oxopyrrolidine-2-methamide; 51) (2S)-4-cyclohexyl-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydro Benzo[f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 52) (2S)-1-(2-(3-Cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f] Imidazo[1,2-d] [1,4]thiazolin-9-yl)-5-oxopyrrolidine-2-carboxamide.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least any one compound represented by formula (I) of the present invention and at least one pharmaceutically acceptable excipient.

The present invention further provides a pharmaceutical composition in which the weight ratio of the compound represented by formula (I) to the adjuvant is in the range of 0.0001-10.

The invention provides the application of the compound represented by the formula (I) or the pharmaceutical composition containing the formula (I) in the preparation of medicines.

The present invention further provides a better technical solution for the application.

Preferably, the drug is used to treat, prevent, delay or prevent the occurrence or progression of cancer or cancer metastasis.

Preferably, the drug is used to treat cancer.

Preferably, the drug is used as a PI3K inhibitor.

Preferably, the drug is used to treat PI3K-mediated diseases.

Preferably, the PI3K includes PI3Kα, PI3Kβ, PI3Kδ and/or PI3Kγ.

Preferably, the PI3K is PI3Kα.

Preferably, the PI3K-mediated disease is cancer.

Preferably, the cancer is selected from the group consisting of sarcoma, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colorectal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, endometrial cancer, melanoma, kidney cancer, Bladder cancer, uterine cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, brain cancer, oral and pharynx cancer, laryngeal cancer, lymphoma, basal cell carcinoma, polycythemia vera, primary thrombocytosis disease.

The present invention also provides a method for treating and/or preventing a patient suffering from a PI3K-mediated disease. The method comprises administering to the patient in need a therapeutically effective amount of at least any one compound represented by formula (I) or containing formula ( Ⅰ) The pharmaceutical composition of the compound shown.

Preferably, in the above method, the PI3K includes PI3Kα, PI3Kβ, PI3Kδ and/or PI3Kγ.

Preferably, in the above method, the PI3K is PI3Kα.

Preferably, in the above method, the PI3K-mediated disease is cancer.

Preferably, in the above method, the cancer is sarcoma, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colorectal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, endometrial cancer, melanoma , Kidney cancer, bladder cancer, uterine cancer, vagina cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, brain cancer, oral and pharynx cancer, laryngeal cancer, lymphoma, basal cell carcinoma, polycythemia vera, the original Thrombocythemia.

The present invention also provides a method for treating cancer, which comprises administering a therapeutically effective amount of at least one compound represented by formula (I) or a pharmaceutical composition containing a compound represented by formula (I) to a subject. The cancer Is sarcoma, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colorectal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, endometrial cancer, melanoma, kidney cancer, bladder cancer, uterine cancer, vagina cancer , Ovarian cancer, multiple myeloma, esophageal cancer, leukemia, brain cancer, oral and pharynx cancer, laryngeal cancer, lymphoma, basal cell carcinoma, polycythemia vera, primary thrombocytosis.

Preferably, in the above method, the subject to be treated is a human being.

The present invention relates to compounds as PI3K inhibitors, and the use of these compounds to prepare drugs for the treatment or prevention of diseases mediated by PI3K in vivo. As an active ingredient, the compound has the characteristics of good therapeutic effect, high selectivity and high bioavailability. As a kind of medicine to be marketed, the compound has the characteristics of low cost and convenient administration, which is more conducive to the wide application of these medicines, and can more effectively help patients overcome pain and improve the quality of life.

The terms used in the present invention have the following meanings.

In the present invention, unless otherwise specified, the term "alkyl" includes linear, branched or cyclic saturated alkyl. For example, alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopentyl and Cyclohexyl. Similarly, "C _{1-4 "in C 1-4} alkyl refers to a group containing 1, 2, 3 or 4 carbon atoms arranged in a linear, branched or cyclic form.

"Cycloalkyl" refers to a cyclic saturated monovalent hydrocarbon group. Similarly, "C _{3-6 "in C 3-6} cycloalkyl refers to a saturated monovalent hydrocarbon group containing 3, 4, 5 or 6 carbon atoms arranged in a cyclic form. Representative cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, or cyclohexane and similar groups.

In the present invention, unless otherwise specified, the term "heterocyclic group" refers to a substituted or unsubstituted non-aromatic 3- to 6-membered monocyclic ring system consisting of a C atom and 1 to 3 selected from N, O or S It is composed of heteroatoms, and N or S heteroatoms can be selectively oxidized, and N heteroatoms can also be quaternized arbitrarily. The heterocycloalkyl group can be attached to any heteroatom or carbon atom that can produce a stable structure. Representative heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, pyridinyl, oxazinyl, oxopazizinyl, oxopyridinyl, oxoazepinyl, nitrogen Heteropyranyl, tetrahydrofuranyl, dioxolane, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl Sulfonyl, thiomorpholinyl and oxadiazolyl.

"Halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). The preferred halogen groups refer to fluorine, chlorine and bromine.

"Halo" refers to a fluoro, chloro, bromo or iodo group.

"Substitution" means that one or more hydrogen atoms in a group are replaced by the same or different substituents. Representative substituents include, but are not limited to, halogen, amino, hydroxy, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, aryl, haloaryl, arylalkyl Group, arylalkenyl, heterocyclyl, cycloalkoxy, alkylamino.

In the present invention, unless otherwise specified, the term "aryl" refers to a substituted or unsubstituted monocyclic or polycyclic ring system containing carbon atoms. The preferred aryl group is phenyl.

In the present invention, unless otherwise specified, the term "heteroaryl" refers to an unsubstituted or substituted stable 5- or 6-membered monoaromatic ring system, or an unsubstituted or substituted 9- or 10-membered benzo-fused Heteroaromatic ring system or double heteroaromatic ring system, the benzo-fused heteroaromatic ring system or double heteroaromatic ring system is composed of carbon atoms and 1 to 4 heteroatoms selected from N, O or S, where N or The S heteroatom can be optionally oxidized, and the N heteroatom can be optionally quaternized. Heteroaryl groups can be attached to any heteroatom or carbon atom that can produce a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, Pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazole Group, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adeninyl, quinolinyl or isoquinolinyl.

The "compound" of the present invention includes the compound of formula (I) and all pharmaceutically acceptable forms thereof. These pharmaceutically acceptable forms include salts, solvates, non-covalent complexes, chelates, stereoisomers (including diastereomers, enantiomers and racemates), geometrically different Conformers, isotopically labeled compounds, tautomers, prodrugs, or any mixture of all the above forms.

The "enantiomers" are a pair of non-superimposable stereoisomers that are mirror images of each other, and a 1:1 mixture of a pair of enantiomers is a "racemic" mixture. When specifying the stereochemistry of the compounds of the present invention, the conventional RS system is used (for example (1S, 2S) specifies a single stereoisomer with two chiral centers of known relative and absolute configuration).

The "diastereomers" are stereoisomers having at least two asymmetric atoms, but they are not mirror images of each other. When the compound is a pure enantiomer, the stereochemistry on each chiral carbon can be designated by R or S.

The resolved compounds with unknown absolute configuration can be named (+) or (-) according to the direction (right-handed or left-handed) they rotate the plane-polarized light at the wavelength of the sodium D line. Alternatively, the resolved compound can be defined by the corresponding retention time of the corresponding enantiomer/diastereomer of chiral HPLC.

Those skilled in the art will recognize that the compounds of the present invention contain chiral centers and therefore can exist in different isomeric forms. Unless otherwise specified, the compounds of the present invention are intended to include all these possible isomers, including racemic mixtures, optically pure forms, and isomer mixtures in any ratio. For example, the compound represented by formula (VIII) includes the compound of Example 2, the compound of Example 32, the compound of Example 33, and the mixture of Example 32 and Example 33 in any ratio. Optically active (R)- and (S)-isomers can be prepared using optically active raw materials synthesis or chiral reagents, or they can be resolved using conventional techniques (for example, separation on a chiral SFC or HPLC column ).

The "pharmaceutically acceptable" refers to those that are well-known for use in animals, especially those that can be used in humans.

The term "composition" in the present invention includes a product containing a specific amount of a specific component, and also includes any product obtained directly or indirectly from a specific amount of a specific component. Therefore, a pharmaceutical composition including the compound of the present invention as an active ingredient and a method for preparing the compound are the content of the present invention. Furthermore, the crystal forms of some compounds may exist in polymorphic forms, and these are also included in the present invention. In addition, some compounds form solvates with water (such as hydrates) or common organic solvents, and such solvates are also included in the present invention.

"Therapeutically effective amount" means that when a compound is administered to a subject to treat and prevent and/or inhibit at least one clinical symptom of a disease, condition, symptom, indication, and/or discomfort, it is sufficient for the disease, condition, symptom, A dose that produces a certain effect for the treatment of indications or discomfort. The specific "therapeutically effective amount" may vary according to the compound, the route of administration, the age of the patient, the weight of the patient, the type, symptoms and severity of the disease or discomfort being treated, etc. Whenever possible, an appropriate dose may be obvious to those skilled in the art, or it may be determined by conventional experimental methods.

The compounds provided by the present invention may also exist in the form of "pharmaceutically acceptable salts". In terms of pharmaceutical applications, the salts of the compounds provided by the present invention refer to non-toxic pharmaceutically acceptable salts. The form of a pharmaceutically acceptable salt includes a pharmaceutically acceptable acid/anion or base/cation salt. Pharmaceutically acceptable acid/anionic salts generally exist in the form of protonation of basic nitrogen with inorganic or organic acids. Typical organic or inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid , Malic acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexylamine sulfonic acid , Salicylic acid, saccharinic acid or trifluoroacetic acid. Pharmaceutically acceptable base/cation salts include, but are not limited to, aluminum salts, calcium salts, chloroprocaine salts, choline, diethanolamine salts, ethylenediamine salts, lithium salts, magnesium salts, potassium salts, sodium salts and Zinc salt.

The "prodrug" of the compound of the present invention is included in the protection scope of the present invention. Generally, the "prodrug" is a functional derivative that is easily converted into the desired compound in the body. Therefore, the term "administration" involved in the treatment method provided by the present invention includes the administration of the compound disclosed in the present invention, or although it is not clearly disclosed but can be transformed into the compound disclosed in the present invention in vivo after administration to the subject to treat various diseases. . Conventional methods for selecting and preparing suitable prodrug derivatives have been described in books such as "Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).

Obviously, the definition of any substituent or variable at a specific position in one molecule is irrelevant to the definition of any substituent or variable at a specific position in other molecules. It is easy to understand that the compound of the present invention can be selected according to the prior art of the subject to select suitable substituents or substitution forms to provide chemically stable and easy preparation and synthesis using the prior art of the subject or the method described in the present invention.

When the compound represented by formula (I) and its pharmaceutically acceptable salt are in the form of a solvate or polymorph, the present invention includes any possible solvate and polymorph. The type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone and similar solvents can be used.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound provided by the present invention is an acid, its corresponding salt can be prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, potassium, sodium, zinc and the like. In particular, salts of ammonium, calcium, magnesium, potassium, and sodium are preferred. The non-toxic organic bases that can be derivatized into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2- Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, haamine, isopropylamine, Lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

When the compound provided by the present invention is a base, the corresponding salt can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , Lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pyruvic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid. Since the compound represented by formula (I) will be used as a pharmaceutical, it is preferable to use a substantially pure form, for example, at least 60% purity, more suitably at least 75% purity, particularly suitably at least 98% purity (% is a weight ratio ).

The pharmaceutical composition provided by the present invention includes a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient, and other optional therapeutic components or adjuvants . Although in any given case, the most suitable way of administering the active ingredient depends on the particular subject to be administered, the nature of the subject and the severity of the disease, the pharmaceutical composition of the present invention includes oral, rectal, topical and Pharmaceutical compositions for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration). The pharmaceutical composition of the present invention can be conveniently prepared in a unit dosage form known in the art and prepared by any preparation method known in the pharmaceutical field.

In fact, according to conventional drug mixing technology, the compound represented by formula (I) of the present invention, or prodrug, or metabolite, or pharmaceutically acceptable salt, can be combined with drugs as the active component and mixed with a drug carrier to form Pharmaceutical composition. The pharmaceutical carrier can take various forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention may take the form of a separate unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention may take the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion or water-in-oil emulsion. In addition, in addition to the common dosage forms mentioned above, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can also be administered by a controlled release method and/or a delivery device. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with the carrier constituting one or more necessary ingredients. In general, the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of the two. In addition, the product can be easily prepared into the desired appearance.

Therefore, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. The compound represented by formula (I), or a pharmaceutically acceptable salt thereof, and one or more other compounds with therapeutic activity in combination are also included in the pharmaceutical composition of the present invention.

The drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier. Examples of solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers include syrup, peanut oil, olive oil and water. Examples of gas carriers; include carbon dioxide and nitrogen. When preparing oral pharmaceutical preparations, any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc. can be used for oral liquid preparations such as suspensions, elixirs and solutions; and carriers, such as starches, sugars, micro Crystal cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. can be used in oral solid preparations such as powders, capsules and tablets. In view of ease of administration, tablets and capsules are preferred for oral preparations. Alternatively, standard aqueous or non-aqueous formulation techniques can be used for tablet coating.

Tablets containing the compound or pharmaceutical composition of the present invention can be prepared by compression or molding together with one or more auxiliary components or adjuvants. The active ingredient is in a free-flowing form such as powder or granules, mixed with lubricants, inert diluents, surface active or dispersing agents, and compressed in a suitable machine to produce compressed tablets. The powdered compound or pharmaceutical composition is soaked with an inert liquid diluent, and then molded in a suitable machine to form a molded tablet. Preferably, each tablet contains about 0.05 mg to 5 g of active ingredient, and each cachet or capsule contains about 0.05 mg to 5 g of active ingredient. For example, a dosage form intended for oral administration to humans contains about 0.5 mg to about 5 g of active ingredients, compounded with suitable and convenient metering auxiliary materials, which make up about 5% to 95% of the total pharmaceutical composition. The unit dosage form generally contains about 1 mg to about 2 g of the effective ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

The pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared as an aqueous solution or suspension by adding active components into water. A suitable surfactant such as hydroxypropyl cellulose may be included. In glycerol, liquid polyethylene glycol, and their mixture in oil, dispersion systems can also be prepared. Furthermore, a preservative may also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.

The present invention provides pharmaceutical compositions suitable for injection use, including sterile aqueous solutions or dispersion systems. Further, the above-mentioned pharmaceutical composition can be prepared in the form of a sterile powder that can be used for immediate preparation of sterile injections. In any case, the final injection form must be sterile, and for easy injection, it must be easy to flow. In addition, the pharmaceutical composition must be stable during preparation and storage. Therefore, preservation against contamination by microorganisms such as bacteria and fungi is preferable. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.

The pharmaceutical composition provided by the present invention may be in a form suitable for topical administration, for example, aerosol, emulsion, ointment, lotion, dusting, or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device. Using the compound represented by formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, these preparations can be prepared by conventional processing methods. As an example, an emulsion or ointment is prepared by adding a hydrophilic material and water to the above compound (the total amount of the two is about 5 wt% to 10 wt% of the compound) to prepare a cream or ointment with the expected consistency .

The pharmaceutical composition provided by the present invention can be made into a form suitable for rectal administration with a solid as a carrier. A unit-dose suppository with the mixture is the best dosage form. Suitable excipients include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared. First, the pharmaceutical composition is mixed with softened or melted excipients, and then cooled and molded.

In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, Lubricants, preservatives (including antioxidants), etc. Further, other adjuvants may also include penetration enhancers that regulate the isotonic pressure between the drug and the blood. The pharmaceutical composition containing the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, can also be prepared in the form of a powder or a concentrated solution.

The present invention will use the following examples to further illustrate the preparation of the compound of formula (I) of the present invention, but there is no limitation to the present invention.

The following examples are only used to illustrate specific implementations of the present invention, so that those skilled in the art can understand the present invention, but are not used to limit the protection scope of the present invention. In the specific embodiments of the present invention, technical means or methods that are not specifically described are conventional technical means or methods in the art. Unless otherwise specified, all parts and percentages in the present invention are calculated by weight, and all temperatures refer to degrees Celsius.

The following abbreviations are used in the examples: DCM: dichloromethane DMF: N,N-dimethylformamide DIEA: N,N-diisopropylethylamine PE: petroleum ether EA: ethyl acetate NIS: N -Iodosuccinimide LCMS or LC-MS: Liquid Mass Spectrometry THF: Tetrahydrofuran DMSO: Dimethyl Sulfylene Et ₃ N or TEA: Triethylamine HATU: 2-(7-Azobenzotriazide Azole)-N,N,N',N'-tetramethylurea hexafluorophosphate Hex: n-hexane h, hr or hrs: hours LiHMDS: lithium bis(trimethylsilyl)amide [PdCl ₂ (dppf) ]CH ₂ Cl ₂ : [1,1'-bis(diphenylphosphine)ferrocene] palladium dichloride dichloromethane complex Boc: tert-butoxycarbonyl min: minutes rt or RT: room temperature. [General Route]

[中間體M-5的製備] [步驟1：化合物M-2的合成]The compound of formula (VI) can be prepared by the following route:

[Preparation of Intermediate M-5] [Step 1: Synthesis of Compound M-2]

Add 4-bromo-2-hydroxybenzaldehyde (40 g) and MeOH (400 mL) into a 1000 mL single-neck flask, add ammonia (136.50 g) dropwise with stirring in an ice bath, and heat the reaction in an oil bath at 35°C. After the LC-MS monitoring to the end of the reaction, the reaction solution was concentrated, diluted with water, extracted with EA four times, the organic phases were combined, dried, concentrated, purified by column chromatography (PE:EA=3:1), and concentrated to obtain 34.55g of compound M -2. LC-MS [M+H ⁺ ]: 239. [Step 2: Synthesis of compound M-3]

Add compound M-2 (34.55 g), Cs ₂ CO ₃ (133 g) and DMF (300 mL) into a 1000 mL single-mouth bottle, stir at room temperature for 20 minutes, and then add 1,2-dibromoethane (54.30 g) dropwise. After the completion, the reaction was refluxed in a 80°C oil bath, and the reaction was monitored by LC-MS until the reaction was complete. The reaction solution was concentrated, diluted with water, extracted three times with EA, the organic phases were combined, dried, concentrated under reduced pressure, purified by column chromatography (PE:EA=70:30), and concentrated to obtain 21.37g of compound M-3. LC-MS [M+H ⁺ ]: 265. ¹ H NMR (500 MHz, chloroform-d) δ 8.38 (d, J = 8.5 Hz, 1H), 7.30-7.15 (m, 3H), 6.99 (s, 1H), 4.47-4.43 (m, 2H), 4.41 -4.35 (m, 2H). [Step 3: Synthesis of compound M-4]

Add compound M-3 (21.37 g) and DMF (100 mL) into a 1000 mL single-neck bottle, stir to dissolve, add NIS (50.78 g) in DMF (100 mL) dropwise to it, and put it in 60℃ oil after the addition is complete. The reaction was carried out overnight in a bath, and after the LC-MS monitoring to the completion of the reaction, water was added to the reaction solution to precipitate a solid, which was filtered off with suction and dried to obtain 35 g of compound M-4. LC-MS [M+H ⁺ ]: 517. ¹ H NMR (500 MHz, Chloroform-d) δ 8.30 (d, J = 8.6 Hz, 1H), 7.25-7.16 (m, 2H), 4.46 -4.41 (m, 2H), 4.36-4.32 (m, 2H) . [Step 4: Synthesis of compound M-5]

Add compound M-4 (35 g) and THF (150 mL) into a 500 mL three-necked flask under nitrogen protection. Add 100 mL ethylmagnesium bromide (1 M THF solution) dropwise to the reaction system at -40°C. After the addition is complete, the reaction is stirred at -40°C. LC-MS monitors until the reaction is complete, quench the reaction by adding saturated ammonium chloride solution under ice bath conditions, add EA for extraction three times, combine the organic phases, dry, concentrate, add methyl tert-butyl ether to make a slurry, filter with suction and dry , 19.8 g of compound M-5 was obtained. LC-MS [M+H ⁺ ]: 391. ¹ H NMR (500 MHz, DMSO-d6) δ 8.22 (d, J = 8.6 Hz, 1H), 7.55 (s, 1H), 7.31 -7.23 (m, 2H), 4.47 -4.39 (m, 4H).

[步驟1：化合物1-3的合成]Example 1 (2S)-1-(2-(5-isopropyl-3-methyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f] Synthesis of imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-carboxamide (compound 1)

[Step 1: Synthesis of Compound 1-3]

Add compound 1-1 (9 g), compound 1-2 (16.8 g), DCM (200 mL) and HATU (31.25 g) into a 500 mL three-necked flask. Add TEA (50.21 g) dropwise to the three-necked flask under ice bath conditions. ), after the addition is complete, react at room temperature. After the reaction was monitored by LC-MS and quenched with water, the organic phase was separated, washed with water, dried over anhydrous Na ₂ SO ₄ , concentrated, and purified by column chromatography (PE:EA=50:50) to obtain 9.2 g of compound 1-3 . LC-MS [M-Boc+H] ⁺ : 131. [Step 2: Synthesis of Compound 1-4]

The HCl/dioxane solution (10 mL, 4.0 mol/L) was added to the dichloromethane (10 mL) solution of compound 1-3 (1.3 g), and the mixture was stirred at room temperature for 3 hours. After the reaction, it was concentrated to obtain 0.9 g of compound 1-4. The compound was directly used in the next reaction without further purification. LC-MS [M+H] ⁺ : 131. [Step 3: Synthesis of Compound 1-5]

Compound 1-4 (900 mg) and TEA (4.19 g) were dissolved in THF (50 mL). Under an ice-water bath, a solution of triphosgene (802 mg) in THF (10 mL) was slowly added dropwise to the reaction system, and the temperature was naturally raised to room temperature and the reaction was stirred for 12 hours. After the reaction was monitored by LCMS, 5 mL of water was added to quench the reaction, concentrated, and dichloromethane/water was added for extraction and liquid separation. The organic phase was dried with anhydrous Na ₂ SO ₄ , concentrated, and purified by column chromatography (PE:EA=1:1) to obtain 732 mg of compound 1-5. LC-MS [M+H] ⁺ : 157. [Step 4: Synthesis of Compound 1-6]

Compound 1-5 (177 mg), compound M-5 (443 mg), CuI (64.75 mg), trans-N,N'-dimethylcyclohexane-1,2-diamine (48.36 mg) And K ₃ PO ₄ (721.68 mg) were dissolved in DMF (5 mL), replaced with nitrogen three times, heated to 110 ℃ and reacted for 2 hours. After LCMS monitoring to the completion of the reaction, add EA (100mL) to dilute the reaction solution, wash the reaction solution with water, combine the organic phases, dry the organic phase with anhydrous Na ₂ SO ₄ , concentrate, and purify by column chromatography (PE:EA=70:30), Obtain 350 mg of compound 1-6. LC-MS [M+H] ⁺ : 419. [Step 5: Synthesis of Compound 1-7]

Compound 1-6 (350 mg), L-proline (290 mg), K ₃ PO ₄ (848 mg), CuI (79.8 mg) and DMSO (5 mL) were added to a 100 mL single-mouth bottle, nitrogen protection, 120 The reaction was stirred at ℃ for 3h. After LCMS monitoring to the completion of the reaction, the reaction solution was filtered, the filter cake was washed with DMSO (3 mL), and the filtrate was directly used in the next step. LC-MS [M+H] ⁺ : 454. [Step 6: Synthesis of Compound 1]

Under nitrogen protection, add DCM (12mL), NH ₄ Cl (445 mg) and DIEA (2.17 g) to the filtrate obtained in step 5, reduce the temperature to 0℃, add HATU (1.27 g) to the reaction system under ice bath conditions , The reaction was stirred at 0°C for 20 min. After LCMS monitoring to the completion of the reaction, the reaction solution was diluted with DCM, washed with water, the organic phase was dried with anhydrous Na ₂ SO ₄ and concentrated, and the crude product obtained was purified by column chromatography (PE:EA=100:0-0:100) to obtain 300 mg of compound 1. LC-MS [M+H] ⁺ : 453. ¹ H NMR (500 MHz, DMSO-d6) δ 8.04 (d, J = 8.9 Hz, 1H), 7.41 (s, 1H), 7.24 (s, 1H), 7.05 (s, 1H), 6.32 (d, J = 8.7 Hz, 1H), 6.03 (s, 1H), 4.62-4.51 (m, 1H), 4.45 -4.30 (m, 4H), 3.94 (d, J = 8.7 Hz, 1H), 3.55 (t, J = 7.3 Hz, 1H), 3.23 (q, J = 7.2 Hz, 1H), 2.92 (s, 3H), 2.68 (m, 1H), 2.26-2.12 (m, 1H), 1.96 (m, 3H), 1.16 ( d, J = 7.0 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H).

[步驟1：化合物2-2的合成]Example 2 (2S)-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f ] Imidazole [1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-carboxamide (compound 2)

[Step 1: Synthesis of compound 2-2]

Add compound 1-1 (5.0 g), DCM (100 mL) and HATU (9.55 g) into a 250 mL single-neck flask, under nitrogen protection, add TEA (8.15 g) and compound 2-1 (1.45 g) under ice bath conditions, React at room temperature for 2h. After the reaction was monitored by LCMS, the reaction solution was concentrated, diluted with EA, washed with water, dried with anhydrous sodium sulfate, and concentrated to obtain 5.0 g of compound 2-2, which was directly used in the next step. LC-MS [M-Boc+H] ⁺ : 157. ¹ H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 6.54 (d, J=9.0 Hz, 1H), 3.69-3.58 (m, 1H), 2.65-2.55 (m, 1H), 1.88 -1.80 (m, 1H), 1.37 (s, 9H), 0.79 (d, J=6.0 Hz, 6H), 0.62-0.58 (m, 2H), 0.42-0.30 (m, 2H). [Step 2: Synthesis of Compound 2-3]

Compound 2-2 (5 g), DCM (20 mL) and HCl/dioxane (20 mL, 4.0 mol/L) were added to a 250 mL single-mouth flask, and reacted at room temperature for 2 h. After the reaction was monitored by LCMS, the reaction solution was concentrated to obtain 3.75 g of compound 2-3. LC-MS [M +H] ⁺ : 157. [Step 3: Synthesis of Compound 2-4]

Compound 2-3 (2.0 g), DCM (50 mL) and TEA (4.20 g) were added to a 250 mL three-neck flask, protected by nitrogen, and triphosgene (1.54 g) was dissolved in DCM ( 50 mL), the reaction was stirred under ice bath for 2h. After the reaction was monitored by LCMS, the reaction was quenched with ice water under ice bath, the reaction solution was concentrated, extracted with EA, dried with anhydrous Na ₂ SO ₄ , concentrated, and the crude product was passed through the column Analytical purification (PE:EA=100:0-50:50), 810 mg of compound 2-4 was obtained. LC-MS [M+H] ⁺ : 183/185. ¹ H NMR (500 MHz, chloroform-d) δ 6.28 (s, 1H), 3.85 (d, J = 3.6 Hz, 1H), 2.66 -2.48 (m, J = 3.7 Hz, 1H), 2.25-2.15 (m , 1H), 1.03 (d, J = 6.5 Hz, 3H), 0.98 -0.91 (m, 4H), 0.88 (d, J = 7.0 Hz, 3H). [Step 4: Synthesis of Compound 2-5]

Add compound 2-4 (431 mg), compound M-5 (700 mg), DMF (10 mL), CuI (102 mg), trans-N,N'-dimethylcyclohexane to a 50mL single-mouth bottle -1,2-Diamine (77 mg) and K ₃ PO ₄ (760 mg), protected by nitrogen, heated to 120°C and stirred for 2 hours. After the reaction was monitored by LCMS, EA was diluted, washed with water, dried with anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (PE:EA=100:0-60:40) to obtain 642 mg of compound 2-5. LC-MS [M+H] ⁺ : 445/447. ¹ H NMR (500 MHz, chloroform-d) δ 8.23 (d, J = 8.5 Hz, 1H), 7.27 (s, 1H), 7.22 (d, J = 8.7 Hz, 1H), 7.20 (s, 1H), 4.63-4.59 (m, 1H), 4.51-4.38 (m, 2H), 4.36 (t, J = 4.3 Hz, 2H), 2.79-2.71 (m, 1H), 2.68-2.60 (m, 1H), 1.24 ( d, J = 7.1 Hz, 3H), 1.02-0.94 (m, 4H), 0.81 (d, J = 6.9 Hz, 3H). [Step 5: Synthesis of Compound 2-6]

Add compound 2-5 (642 mg), compound M-12 (415 mg), K ₃ PO ₄ (919 mg) and DMSO (10 mL) into a 30 mL microwave tube, purge with nitrogen, and add CuI (83 mg ), the temperature was raised to 120°C for microwave reaction for 1 hour. After the reaction is monitored by LCMS, the reaction solution is directly used in the next step. LC-MS [M+H] ⁺ : 480. [Step 6: Synthesis of Compound 2]

Add the reaction solution obtained in step 5 to a 50mL single-neck flask, replace with nitrogen, add DCM (10mL), NH ₄ Cl (462 mg) and TEA (1.46 g), cool the reaction system to 0°C, add HATU( 3.28 g), the reaction was stirred at 0°C for 1h. After the reaction was monitored by LCMS, the reaction solution was diluted with DCM, washed with water, and the organic phase was dried with anhydrous Na ₂ SO ₄ and concentrated. The crude product obtained was purified by Pre-HPLC (C18 column, H ₂ O:MeOH=95:5-50:50 ) To obtain 85 mg of compound 2. LC-MS [M+H] ⁺ : 479. ¹ H NMR (500 MHz, DMSO-d6) δ 8.03 (d, J = 9.0 Hz, 1H), 7.40 (s, 1H), 7.24 (s, 1H), 7.05 (s, 1H), 6.32 (d, J = 8.9 Hz, 1H), 6.03 (d, J = 2.6 Hz, 1H), 4.48 (s, 1H), 4.41 -4.29 (m, 4H), 3.94 (d, J = 8.8 Hz, 1H), 3.55 (t , J = 8.1 Hz, 1H), 3.25-3.19 (m, 1H), 2.74 -2.55 (m, 2H), 2.25-2.14 (m, 1H), 2.07-1.85 (m, 3H), 1.13 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 7.2 Hz, 2H), 0.81 (d, J = 3.9 Hz, 2H), 0.71 (d, J = 6.8 Hz, 3H). [Step 7: Preparation of Compound 32 and Compound 33]

In this embodiment, by resolving compound 2 on a chiral column under the following conditions, compound 32 (pre-peak) and compound 33 (post-peak) can be obtained. [Chiral HPLC conditions] Column CHIRALPAK IA Column specifications 3cm×25cm, 5um Injection volume 4.0mL Mobile phase (Hex:DCM =3:1):EtOH=50:50 (v/v) Flow rate 35mL/min wavelength UV 220 nm temperature 25℃ Sample solution 12.3mg/mL EtOH:DCM=3:1 solution Prepare HPLC equipment Prep-HPLC-flash Compound 32: LC-MS [M+H] ⁺ : 479. ¹ H NMR (500 MHz, DMSO-d6) δ 8.03 (d, J = 9.0 Hz, 1H), 7.40 (s, 1H), 7.24 (s, 1H), 7.05 (s, 1H), 6.32 (d, J = 8.9 Hz, 1H), 6.03 (d, J = 2.6 Hz, 1H), 4.48 (s, 1H), 4.41 – 4.29 (m, 4H), 3.94 (d, J = 8.8 Hz, 1H), 3.55 (t , J = 8.1 Hz, 1H), 3.25-3.19 (m, 1H), 2.74 – 2.55 (m, 2H), 2.25-2.14 (m, 1H), 2.07-1.85 (m, 3H), 1.13 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 7.2 Hz, 2H), 0.81 (d, J = 3.9 Hz, 2H), 0.71 (d, J = 6.8 Hz, 3H). Compound 33: LC-MS [ M+H] ⁺ : 479. ¹ H NMR (500 MHz, DMSO-d6) δ 8.03 (d, J = 9.0 Hz, 1H), 7.40 (s, 1H), 7.24 (s, 1H), 7.05 (s, 1H), 6.32 (d, J = 8.9 Hz, 1H), 6.03 (d, J = 2.6 Hz, 1H), 4.48 (s, 1H), 4.41 – 4.29 (m, 4H), 3.94 (d, J = 8.8 Hz, 1H), 3.55 (t , J = 8.1 Hz, 1H), 3.25-3.19 (m, 1H), 2.74 – 2.55 (m, 2H), 2.25-2.14 (m, 1H), 2.07-1.85 (m, 3H), 1.13 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 7.2 Hz, 2H), 0.81 (d, J = 3.9 Hz, 2H), 0.71 (d, J = 6.8 Hz, 3H).

[步驟1：化合物3-2的合成]Example 3 (2S)-1-(2-(5-isopropyl-2,4-dioxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-yl)-5 Synthesis of ,6-dihydrobenzo[f]imidazole[1,2-d][1,4]oxazepine-9-yl)pyrrolidine-2-methanamide (compound 3)

[Step 1: Synthesis of compound 3-2]

Compound 3-0 (2 g) and compound 3-1 (583 mg) were added to DCM (100 ml), HATU (2.67 g) and DIEA (2.28 g) were added to the reaction system in turn, and the reaction was stirred at room temperature for 12 h. Water was added to the reaction solution, the layers were separated and concentrated to obtain a residue. Ethyl acetate (25 mL) was added to the residue, washed with water and saturated brine, the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated to obtain 1.8 g of product. LC-MS [M+H] ⁺ : 421. [Step 2: Synthesis of compound 3-3]

Diethylamine (10 mL) was added to the solution of compound 3-2 (1.8 g) dissolved in DCM (10 ml), and stirred at room temperature for 2 h. The residue was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 0.70 g of compound 3-3. LC-MS [M+H] ⁺ : 199. [Step 3: Synthesis of Compound 3-4]

_{Add compound 3-3 (200 mg), CH 3} CN (10 mL), NaHCO ₃ (254 mg), and replace with nitrogen three times into a 50 mL three-necked flask. Add p-nitrophenyl chloroformate (203 mg) to it. The reaction was stirred at warm temperature for 2 hours. Then 6 mL of water was added to the reaction system, and the reaction was stirred at room temperature for 3 hours. After the completion of the reaction, the residue was concentrated under reduced pressure, and the residue was diluted with EA. The organic phase was washed successively with water, potassium carbonate aqueous solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE:EA=60:40) to obtain 195 mg of compound 3-4. LC-MS [M+H] ⁺ : 225. [Step 4: Synthesis of Compound 3-5]

Compound 3-4 (138 mg), compound M-5 (200 mg), CuI (39 mg), trans-N,N'-dimethylcyclohexane-1,2-diamine (29 mg) , K ₃ PO ₄ (326 mg) was dissolved in DMF (5 mL), replaced with nitrogen three times, and the reaction was heated to 110°C for 2 hours. After the reaction is completed, add EA to the reaction mixture to dilute, wash once with water, and wash three times with saturated brine. The organic phase is dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA=100:0-70:30) to obtain 180 mg compound 3-5. LC-MS [M+H ⁺ ]: 487/489. [Step 5: Synthesis of compound 3-6]

Add compound 3-5 (117 mg), compound M-12 (138 mg), K ₃ PO ₄ (356 mg), CuI (46 mg) and DMSO (3 mL) into a 50 mL single-necked flask, replace with nitrogen three times, and warm to The reaction was stirred at 120°C for 3 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with DMSO (3 mL), and the filtrate was directly used in the next step. LC-MS [M+H] ⁺ : 522. [Step 6: Synthesis of Compound 3]

Under the protection of nitrogen, DCM (6 mL), NH ₄ Cl (127 mg), DIEA (613 mg) were added to the filtrate obtained in step 5, the reaction solution was cooled to 0°C, and HATU was added to it in batches under ice bath. (447 mg), the reaction was stirred at 0°C for 20 min. After the reaction, the reaction solution was diluted with dichloromethane, washed with water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by Pre-HPLC to obtain 85 mg of compound 3. LC-MS [M+H] ⁺ : 521. ¹ H NMR (500 MHz, DMSO-d6) δ 8.05 (d, J = 8.5 Hz, 1H), 7.41 (s, 1H), 7.29 (s, 1H), 7.06 (s, 1H), 6.33 (d, J = 9 Hz, 1H), 6.04 (s, 1H), 4.71 – 4.70 (m, 1H), 4.38 – 4.24 (m, 6H), 3.95 (d, J = 8.5 Hz, 1H), 3.55 (t, J = 7.3 Hz, 1H), 3.28-3.20 (m, 1H), 2.70 (brs, 1H), 2.25-2.15(m, 1H), 2.00-1.94(m, 3H), 1.17 (d, J = 7.0 Hz, 3H ), 0.75 (d, J = 7 Hz, 3H).

[步驟1：化合物4-1的合成]Example 4 (2S)-1-(2-(3-(4-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydro Synthesis of Benzo[f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide (Compound 4)

[Step 1: Synthesis of compound 4-1]

To a solution of compound 1-1 (1.5 g) and p-fluoroaniline (921 mg) in DCM (50 ml) was added HATU (3.39 g) and DIEA (2.68 g). The reaction solution was stirred at room temperature for 12 h. After the completion of the reaction, the reaction solution was diluted with water and separated, the organic phase was washed with 1 N HCl, NaHCO ₃ saturated aqueous solution and saturated brine successively, the organic phase was dried with anhydrous Na ₂ SO ₄ and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA / PE =0-30%) to obtain 2.1 g of compound 4-1. LC-MS [M-Boc+H] ⁺ : 211. [Step 2: Synthesis of compound 4-2]

Compound 4-1 (2.1 g) was added to the HCl/dioxane (10 mL, 4 M) solution and stirred at room temperature for 12 h. Concentrated under reduced pressure to obtain 1.64 g of compound 4-2, which was used directly in the next reaction without further purification. LC-MS [M+H] ⁺ : 211. [Step 3: Synthesis of compound 4-3]

Add compound 4-2 (500 mg), CH ₃ CN (30 mL), NaHCO ₃ (681 mg), nitrogen replacement three times into a 50 mL three-necked flask, and then add p-nitrophenyl chloroformate (449 mg) to it, The reaction was stirred at room temperature for 2 hours. 18 mL of water was added to the reaction solution, and the reaction was stirred at room temperature for 3 hours.

After the reaction, the residue was concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL). The organic phase was washed with water (50 mL), 5% K ₂ CO ₃ aqueous solution (50 mL) and saturated brine, and separated. The organic phase was dried with anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA/PE=0-40%) to obtain 447 mg of compound 4-3. LC-MS [M+H] ⁺ : 237. [Step 4: Synthesis of compound 4-4]

Compound 4-3 (144 mg), compound M-5 (200 mg), CuI (39 mg), trans-N,N'-dimethylcyclohexane-1,2-diamine (29 mg) , K ₃ PO ₄ (326 mg) was dissolved in DMF (5 mL), replaced with nitrogen three times, heated to 110C and reacted for 2 hours. After the reaction is complete, add ethyl acetate (100mL) to dilute the reaction solution, wash the organic phase with water (60mL) and saturated brine (60mL) successively, dry the organic phase with anhydrous sodium sulfate, concentrate, and column chromatography (PE:EA=100 :0-70:30) to obtain 215 mg of compound 4-4. LC-MS [M+H] ⁺ : 499. [Step 5: Synthesis of Compound 4-5]

Add 4-4 (120 mg), compound M-12 (138 mg), K ₃ PO ₄ (356 mg), CuI (46 mg) and DMSO (3 mL) to a 100 mL single-neck bottle, replace with nitrogen three times, and heat to 120 The reaction was stirred at °C for 3 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with 3 mL DMSO, and the filtrate was directly used in the next step. LC-MS [M+H ⁺ ]: 534. [Step 6: Synthesis of Compound 4]

Under nitrogen protection, DCM (12mL), NH ₄ Cl (445 mg) and DIEA (2.17 g) were added to the filtrate obtained in step 5, the temperature of the reaction solution was cooled to 0℃, and HATU (1.27 g) was added to it in batches under ice bath. ), then the reaction was stirred at 0°C for 20 min. After the completion of the reaction, the reaction solution was diluted with DCM (50 mL), the organic phase was washed with water (40 mL) and saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE:EA=100:0-0:100) to obtain 89 mg of compound 4. LC-MS [M+H] ⁺ : 533. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.08 (d, J = 8.9 Hz, 1H), 7.45-7.41 (m, 3H), 7.38-7.35 (m, 2H), 7.28 (s, 1H), 7.06 (s, 1H), 6.34 (d, J = 8.9 Hz, 1H), 6.04 (s, 1H), 4.76 (s, 1H), 4.40-4.37 (m, 4H), 3.95 (d, J = 8.8 Hz , 1H), 3.60-3.52 (m, 1H), 3.24 (q, J = 8.5, 7.7 Hz, 1H), 2.75 (s, 1H), 2.26 – 2.14 (m, 1H), 2.00-1.93 (m, 3H ), 1.22 (d, J = 7.1 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H).

Using a resolution method similar to step 7 of Example 2, compound 30 and compound 31 can be prepared.

Example 5 (2S)-1-(2-(5-cyclopropyl-3-methyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f] Synthesis of imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-carboxamide (compound 5)

Replace compound 1-1 with compound 5-0, replace p-fluoroaniline with methylamine hydrochloride, and use a preparation method similar to that of Example 4 to obtain compound 5. LC-MS [M+H] ⁺ : 451.

Example 6 (2S)-1-(2-(3-cyclobutyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f ] Imidazo[1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-carboxamide (compound 6)

Substituting p-fluoroaniline with cyclobutylamine, and using a preparation method similar to that in Example 4, compound 6 can be obtained. LC-MS [M+H] ⁺ : 493. ¹ H NMR (500 MHz, DMSO-d6) δ 8.04 (d, J = 9 Hz, 1H), 7.41 (s, 1H), 7.25 (s, 1H), 7.05 (s, 1H), 6.32 (d, J = 9 Hz, 1H), 6.03 (s, 1H), 4.52 – 4.48 (m, 1H), 4.37 – 4.35 (m, 4H), 3.94 (d, J = 8.5 Hz, 1H), 3.55 (t, J = 7 Hz, 1H), 3.23 (q, J = 7.2 Hz, 1H), 2.80-2.65 (m, 3H), 2.14 – 2.12 (m, 3H), 1.96 -1.94 (m, 3H), 1.79-1.71 (m , 3H), 1.15 (d, J=7 Hz, 3H) 0.74 (d, J = 6.5 Hz, 3H).

Example 7 (2S)-1-(2-(3-ethyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f] Synthesis of imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-carboxamide (compound 7)

Compound 3-1 is replaced with compound 7-1, and compound 7 can be obtained by using a preparation method similar to that of Example 3. LC-MS [M+H] ⁺ : 467.

(2S)-1-(2 -(5-二氟甲基-3-甲基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4] 氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 461 9

(2S)-1-(2-(5-異丙基-2,4-二氧代-3-苯基咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4] 氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 515 10

(S)-1-(2-((S)-5-異丙基-2,4-二氧代-3-苯基咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 515 11

(S)-1-(2-((R)-5-異丙基-2,4-二氧代-3-苯基咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 515 12

(2S)-1-(2-(5-異丙基-2,4-二氧代-3-(4-(三氟甲基)苯基)咪唑烷-1-基)-5,6-二氫苯并[f]咪唑[1,2 -d] [1,4] 氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 583 13

(2S)-1-(2-(5-異丙基-2,4-二氧代-3-丙基咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4] 氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 481 14

(2S)-1-(2-(3-環丙基-5-異丙基)-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4] 氧氮雜䓬-9-基)-2-甲基吡咯烷-2-甲醯胺 493 15

(2S)-1-(2-(3-環丙基-5-異丙基)-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4] 噻唑啉-9-基)-4,4-二氟吡咯烷-2-甲醯胺 531 16

(2S)-1-(2-(5-異丙基-3-(1-甲基-1H-1,2,4-三唑-5-基)-2,4-二氧代咪唑烷-1-基)-5,6 -二氫苯并[f]咪唑并[1,2-d] [1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 520 17

(2S,4S)-4-氨基-1-(2-(3-環丙基-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑[1,2-d ] [1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 494 18

(2S)-1-(2-(3-(2-氟苯基)-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑[1,2-d] [ 1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 533 19

(2S)-1-(2-(3-(4-氯苯基)-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [ 1,4] 氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 549 20

(2S)-4-(叔丁氧基)-1-(2-(3-環丙基-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑[1,2] -d] [1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 551 21

(2S)-1-(2-(3-環丙基-5-異丙基)-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4]氧氮雜䓬-9-基)-4,4-二甲基吡咯烷-2-甲醯胺 507 22

(2S)-1-(2-(3-(2,2-二氟乙基)-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d ] [1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 503 23

(2S)-1-(2-(3,5-二異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4] 氧氮雜䓬- 9-基)吡咯烷-2-甲醯胺 481 24

(2S)-1-(2-(3-環丙基-5-異丙基)-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4]氧氮雜䓬-9-基)-4-苯基吡咯烷-2-甲醯胺 555 25

(2S)-1-(2-(3-(3-氯5-氰基苯基)-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2 -d] [1,4] 噻唑啉-9-基)吡咯烷-2-甲醯胺 590 26

(2S)-1-(2-(3,5-二異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4]噻唑啉- 9-基)吡咯烷-2-甲醯胺 497 27

(2S)-1-(2- (3-氮雜環丁烷-3-基)-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d ] [1,4] 氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 494 28

(2S)-1-(2-(3-甲基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4] 氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 411 29

(2S)-1-(2- (5-叔丁基-3-甲基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [ 1,4] 氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 467 30

(S)-1-(2-((R)-3-(4-氟苯基)-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2]-d] [1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 533 31

(S)-1-(2-((S)-3-(4-氟苯基)-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2] -d] [1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 533 32

(2S)-1-(2-((5R)-3-環丙基-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [ 1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 479 33

(2S)-1-(2-((5S)-3-環丙基-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [ 1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 479 34

(2S)-1-(2-(3-(2-羥乙基)-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [ 1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 483 35

(2S)-1-(2-(3-(2-氟乙基)-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 485 36

(2S)-1-(2-(3-(2-(二甲基氨基)乙基)-5-)異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2- d] [1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 510 37

(2S)-1-(2-(3-環丙基-5-異丙基)-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4]噻唑啉-9-基)吡咯烷-2-甲醯胺 495 38

(2S)-1-(2-(3-(6-氟吡啶-3-基)-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2 -d] [1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 534 39

(2S)-1-(2-(3-(5-氟吡啶-3-基)-5-異丙基-2,4-二氧代咪唑烷1-基)-5,6-二氫苯并[f]咪唑并[1,2] -d] [1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 534 40

(2S)-1-(2-(3-(3-氰基-5-氟苯基)-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2 -d] [1,4]氧氮雜䓬-9-基)-4-氟吡咯烷-2-甲醯胺 576 41

(2S)-1-(2-(3-(3-氯嘧啶-2-基)-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2 -d] [1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 551 42

(2S)-1-(2-(3-環戊基-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑[1,2-d] [1,4] 氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 507 43

(2S)-1-(2-(3-(氰基甲基)-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 478 44

(2S)-1-(2-(5-異丙基-3-甲基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4] 噻唑啉-9-基)吡咯烷-2-甲醯胺 469 45

(2S)-1-(2-(3-(2,2-二氟乙基)-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d ] [1,4]噻唑啉-9-基)吡咯烷-2-甲醯胺 519 46

(2S)-1-(2-(3-環丙基-5-異丙基-2,4-二氧代咪唑烷-1-基)-3-乙烯基-5,6-二氫苯并[f]咪唑并[1,2-d] [ 1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 505 47

(2S)-1-(3-氯-2-(3-環丙基-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [ 1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 513 48

(2S)-1-(2-(3-環丙基-5-(二氟甲基)-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1, 4]噻唑啉-9-基)吡咯烷-2-甲醯胺 503 49

(2S,3S)-1-(2-(3-環丙基-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4]氧氮雜䓬-9-基)-3-羥基吡咯烷-2-甲醯胺 495 50

(2S)-1-(2-(3-環丙基-5-異丙基-2,4-二氧代咪唑烷-1-基)-3-甲基-5,6-二氫苯并[f]咪唑并[1,2-d] [ 1,4]氧氮雜䓬-9-基)-4-氧代吡咯烷-2-甲醯胺 507 51

(2S)-4-環己基-1-(2-(3-環丙基-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4]氧氮雜䓬-9-基)吡咯烷-2-甲醯胺 561 52

(2S)-1-(2-(3-環丙基-5-異丙基-2,4-二氧代咪唑烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d] [1,4] 噻唑啉-9-基)-5-氧代吡咯烷-2-甲醯胺 509 Using different reaction starting materials and appropriate reagents, the compounds in the examples in Table 1 were prepared using methods similar to those in Examples 1-7. [Table 1] Example number structure Chemical naming LCMS[M+H] ⁺ 8

(2S)-1-(2-(5-Difluoromethyl-3-methyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazo [1,2-d] [1,4] Oxazepine-9-yl)pyrrolidine-2-carboxamide 461 9

(2S)-1-(2-(5-isopropyl-2,4-dioxo-3-phenylimidazolidin-1-yl)-5,6-dihydrobenzo(f)imidazo[ 1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-carboxamide 515 10

(S)-1-(2-((S)-5-isopropyl-2,4-dioxo-3-phenylimidazolidin-1-yl)-5,6-dihydrobenzo(f ]Imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-carboxamide 515 11

(S)-1-(2-((R)-5-isopropyl-2,4-dioxo-3-phenylimidazolidine-1-yl)-5,6-dihydrobenzo(f ]Imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-carboxamide 515 12

(2S)-1-(2-(5-isopropyl-2,4-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)-5,6- Dihydrobenzo[f]imidazole[1,2 -d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide 583 13

(2S)-1-(2-(5-isopropyl-2,4-dioxo-3-propylimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazo[ 1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-carboxamide 481 14

(2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole And [1,2-d] [1,4] oxazepine-9-yl)-2-methylpyrrolidin-2-methamide 493 15

(2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole And [1,2-d] [1,4]thiazolin-9-yl)-4,4-difluoropyrrolidine-2-methamide 531 16

(2S)-1-(2-(5-isopropyl-3-(1-methyl-1H-1,2,4-triazol-5-yl)-2,4-dioxoimidazolidine- 1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide 520 17

(2S,4S)-4-amino-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzene And [f]imidazole[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide 494 18

(2S)-1-(2-(3-(2-Fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[ f]imidazole[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-carboxamide 533 19

(2S)-1-(2-(3-(4-chlorophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[ f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide 549 20

(2S)-4-(tert-butoxy)-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6- Dihydrobenzo[f]imidazole[1,2] -d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide 551 twenty one

(2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole And [1,2-d] [1,4]oxazepine-9-yl)-4,4-dimethylpyrrolidine-2-methamide 507 twenty two

(2S)-1-(2-(3-(2,2-Difluoroethyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydro Benzo[f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide 503 twenty three

(2S)-1-(2-(3,5-Diisopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazo[1, 2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-carboxamide 481 twenty four

(2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole And [1,2-d] [1,4]oxazepine-9-yl)-4-phenylpyrrolidine-2-methanamide 555 25

(2S)-1-(2-(3-(3-chloro5-cyanophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-di Hydrobenzo[f]imidazo[1,2 -d] [1,4]thiazolin-9-yl)pyrrolidine-2-methamide 590 26

(2S)-1-(2-(3,5-Diisopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazo[1, 2-d] [1,4]thiazolin-9-yl)pyrrolidine-2-carboxamide 497 27

(2S)-1-(2- (3-azetidin-3-yl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydro Benzo[f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide 494 28

(2S)-1-(2-(3-Methyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazo[1,2-d] [1,4] Oxazepine-9-yl)pyrrolidine-2-carboxamide 411 29

(2S)-1-(2-(5-tert-butyl-3-methyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazo[ 1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-carboxamide 467 30

(S)-1-(2-((R)-3-(4-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-di Hydrobenzo[f]imidazo[1,2]-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide 533 31

(S)-1-(2-((S)-3-(4-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-di Hydrobenzo[f]imidazo[1,2] -d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide 533 32

(2S)-1-(2-((5R)-3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[ f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-carboxamide 479 33

(2S)-1-(2-((5S)-3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[ f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-carboxamide 479 34

(2S)-1-(2-(3-(2-hydroxyethyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[ f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-carboxamide 483 35

(2S)-1-(2-(3-(2-Fluoroethyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[ f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide 485 36

(2S)-1-(2-(3-(2-(dimethylamino)ethyl)-5-)isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6 -Dihydrobenzo[f]imidazo[1,2- d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide 510 37

(2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole And [1,2-d] [1,4]thiazolin-9-yl)pyrrolidine-2-methanamide 495 38

(2S)-1-(2-(3-(6-Fluoropyridin-3-yl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydro Benzo[f]imidazo[1,2 -d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide 534 39

(2S)-1-(2-(3-(5-fluoropyridin-3-yl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzene And [f]imidazo[1,2] -d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide 534 40

(2S)-1-(2-(3-(3-cyano-5-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6- Dihydrobenzo[f]imidazo[1,2 -d] [1,4]oxazepine-9-yl)-4-fluoropyrrolidine-2-methamide 576 41

(2S)-1-(2-(3-(3-chloropyrimidin-2-yl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydro Benzo[f]imidazo[1,2 -d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide 551 42

(2S)-1-(2-(3-cyclopentyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole[ 1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-carboxamide 507 43

(2S)-1-(2-(3-(cyanomethyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f ]Imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-carboxamide 478 44

(2S)-1-(2-(5-isopropyl-3-methyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazo[ 1,2-d] [1,4]thiazolin-9-yl)pyrrolidine-2-carboxamide 469 45

(2S)-1-(2-(3-(2,2-Difluoroethyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydro Benzo[f]imidazo[1,2-d] [1,4]thiazolin-9-yl)pyrrolidine-2-carboxamide 519 46

(2S)-1-(2-(3-Cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-3-vinyl-5,6-dihydrobenzo [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide 505 47

(2S)-1-(3-Chloro-2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[ f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-carboxamide 513 48

(2S)-1-(2-(3-cyclopropyl-5-(difluoromethyl)-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f ]Imidazo[1,2-d] [1, 4]thiazolin-9-yl)pyrrolidine-2-carboxamide 503 49

(2S,3S)-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f] Imidazo[1,2-d] [1,4]oxazepine-9-yl)-3-hydroxypyrrolidin-2-methamide 495 50

(2S)-1-(2-(3-Cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-3-methyl-5,6-dihydrobenzo [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)-4-oxopyrrolidine-2-methamide 507 51

(2S)-4-cyclohexyl-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide 561 52

(2S)-1-(2-(3-Cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazo [1,2-d] [1,4] Thiazolin-9-yl)-5-oxopyrrolidine-2-methamide 509

2 (2S)-1-(2-((2R)-2-(羥甲基)-5-氧吡咯烷-1-基)-5,6-二氫苯并[f]咪唑并[1,2-d][1,4] 氧氮雜䓬-9-基)吡咯烷-2-甲醯胺

3 (2S)-1-(2-(2-(1,1,1-三氟-2-甲基丙-2-基)吡啶-4-基)-5,6-二氫苯并[f]咪唑[1,2-d][1,4] 氧氮雜䓬-9-基)吡咯烷-2-甲醯胺

All the racemate compounds in Table 1 can be synthesized and prepared using corresponding chiral raw materials to obtain the corresponding enantiomers, or basically follow the method described in step 7 of Example 2 to separate the enantiomers on a chiral column. body. [Comparative example] [Table 2] Comparative example number Compound name structure 1 (2S)-1-(2-((4R)-4-methyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo(f)imidazo[1,2- d] [1,4] oxazepine-9-yl)pyrrolidine-2-carboxamide

2 (2S)-1-(2-((2R)-2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)-5,6-dihydrobenzo(f)imidazo[1,2 -d][1,4] oxazepine-9-yl)pyrrolidine-2-methamide

3 (2S)-1-(2-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)-5,6-dihydrobenzo(f) Imidazole[1,2-d][1,4]oxazepine-9-yl)pyrrolidine-2-methamide

[步驟1：化合物D3-2的合成]Refer to the preparation method of Example 102 in WO2017001658, and use the corresponding starting materials, intermediates and appropriate reagents to obtain the compounds of Comparative Example 1 (Example 102 in WO2017001658) and Comparative Example 2 in Table 2; Comparative Example 3 The preparation method of the compound is shown below. [Preparation of Comparative Example 3]

[Step 1: Synthesis of compound D3-2]

Compound D3-1 (2000 g) and oxalic chloride (2019 g) were dissolved in dichloromethane (8 L), DMF (5 mL) was slowly added dropwise to the reaction system, and the reaction was refluxed for 6 hours. The reactant was concentrated to obtain 2245 g of suspension containing yellow solid, which was directly used in the next reaction. [Step 2: Synthesis of compound D3-3]

4-Methoxy-3-butene-2-one (642 g) was dissolved in anhydrous THF (16 L) solution, and 6.42 L of LiHMDS (1 mol/ L) The solution is added dropwise to the reaction system. Stir at -78°C for 2 hours, slowly add dropwise a solution of the suspension obtained in step 1 dissolved in anhydrous THF (1 L) into the system, stir at -78°C for 1-2 hours, then warm to room temperature and stir for 16 hours , The obtained reaction solution is directly used for the next step reaction. LC-MS [M+H] ⁺ : 239. [Step 3: Synthesis of compound D3-4]

The reaction solution obtained in step 2 was quenched by adding water (500 mL) in an ice-water bath, then trifluoroacetic acid (50 mL) was added, and stirring was continued for 3 hours at room temperature. After the reaction, the system was concentrated and extracted with EA. The organic phase was washed with brine, dried with anhydrous Na ₂ SO ₄ , concentrated, and purified by column chromatography (Hex/EA 100:1-10:1) to obtain a brown solid. The solid was replaced with a mixed solution of HEX and EA (volume ratio 50:1) It was washed, filtered with suction, and the filtrate was collected and concentrated to obtain 395 g of compound D3-4. LC-MS [M+H] ⁺ : 207. ¹ H NMR (MeOD-d6): 1.59 (s, 6H), 6.39-6.41 (m, 1H), 6.53-6.54 (m, 1H), 8.12-8.14 (m, 1H). [Step 4: Synthesis of compound D3-5]

Compound D3-4 (395 g) was added to 2 L of aqueous ammonia solution (30%), and the reaction was stirred at reflux for 2 hours. The reaction solution was cooled and concentrated to obtain 343.00 g of compound D3-5, which was directly used in the next step. LC-MS [M+H] ⁺ : 206. [Step 5: Synthesis of compound D3-6]

A mixture of compound D3-5 (343 g) and phosphorus oxybromide (966.68 g) was heated and stirred at 120°C for 1 hour. Pour the reaction solution into ice water while it is hot, add sodium bicarbonate, adjust the pH to neutral, extract with EA, dry and concentrate the organic phase, and purify by column chromatography (Hex/EA=100:1) to obtain 305 g of compound D3-6. LC-MS [M+H] ⁺ : 269. ¹ H NMR (MeOD-d6): 1.59 (s, 6H), 7.52-7.54 (m, 1H), 7.78 (s, 1H), 8.41-8.42 (m, 1H). [Step 6: Synthesis of compound D3-7]

Take a single-mouth bottle and add pinacol diborate (710.45 mg), compound D3-6 (500 mg), potassium acetate (1.88 g), [PdCl ₂ (dppf)]CH ₂ Cl ₂ (152.32 mg) and dioxane Ring (20 mL), protected by nitrogen, reacted in an oil bath at 90°C for 4 hours, concentrated the reaction solution, and purified by column chromatography (Hex/EA=3:1) to obtain 450 mg of compound D3-7. LC-MS [M+H] ⁺ : 316. [Step 7: Synthesis of compound D3-8]

Add [PdCl ₂ (dppf)]CH ₂ Cl ₂ (233.22 mg), potassium carbonate (394.70 mg), compound D3-7 (450 mg), compound M-5 (586.25 mg), dioxane ( 3 mL) and H ₂ O (0.5 mL), protected by nitrogen, refluxed in an oil bath at 70°C for 15 hours, concentrated the reaction solution, and purified by column chromatography (PE:EA=50:50) to obtain 130 mg of compound D3-8. LC-MS [M+H] ⁺ : 452. [Step 8: Synthesis of compound D3-9]

Refer to the method of step 5 in Example 2 to obtain compound D3-9. LC-MS [M+H] ⁺ : 487. [Step 9: Synthesis of Comparative Example 3]

Refer to the method of step 6 in Example 2 to obtain the compound of Comparative Example 3. LC-MS [M+H] ⁺ : 486. [Pharmacological test]

The following experiments show that the preferred compounds of the present invention can effectively inhibit the activity of PI3Kα kinase in vitro. The anti-PI3Kα mutant tumor cell proliferation activity and the pharmacokinetic test results of the preferred compound of the present invention are better than those of the control example, and have significant progress. [Example A: Kinase Test]

PI3Kα, PI3Kβ, PI3Kγ kinases and their substrates ATP, PIP2:3PS are used for enzymatic reactions, and the amount of the product is detected by ADP-Glo reagent and luminescence method to reflect the enzymatic activity of PI3Kα, PI3Kβ, PI3Kγ (ATP final concentration 10 μM) . The above method was used to test the inhibitory activity of some compounds of the present invention on PI3Kα, PI3Kβ and PI3Kγ kinases. [Detection method]

Reagents: basic kinase buffer (pH 7.5); PI3Kα, PI3Kβ, PI3Kγ enzyme solutions; PIP2:3PS and ATP solutions; ADP-Glo kit (containing 10 mM MgCl ₂ ).

Among them, the buffer components: 50 mM Hepes (pH 7.2-7.5), 3 mM MgCl ₂ , 1 mM EGTA, 0.03% CHAPS, 100 mM NaCl, 2 mM DTT.

Prepare the compound: Use 100% DMSO to dilute the test compound to a specific concentration.

[Reaction process] 1) Add PI3Kα, PI3Kβ, and PI3Kγ protein solutions to the 384 reaction plate (6008280, PerkinElmer), and centrifuge at 1000 rpm for 1 minute for later use. 2) Add the compound to be tested, the negative control DMSO or the positive control BYL719, to the above-mentioned enzyme-added 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 15 minutes. 3) Add PIP2:3PS&ATP solution to the above 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 60 minutes. 4) Transfer 5 μL of ADP-Glo reagent (containing 10 mM MgCl ₂ ) to a 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes. 5) Transfer 10 μL of Detection reagent to 384 reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 40 minutes. 6) Use Envision multi-function plate reader to read Relative Luminescence Unit (RLU) value. The RLU value is used to characterize the degree of reaction between the enzyme and the substrate, and to calculate the IC ₅₀ value. 7) Experimental data processing process: Compound inhibition rate (% inh)=(negative control RLU-compound to be tested RLU)/(negative control RLU-positive control RLU)*100%.

Use the following nonlinear fitting formula to obtain the IC ₅₀ (half inhibition concentration) of the compound: Y=minimum inhibition rate + (maximum inhibition rate-minimum inhibition rate)/(1+10^((LogIC ₅₀ -X)*slope) ); where X is the log value of the concentration of the compound to be tested, and Y is the inhibition rate of the compound to be tested (% inh).

The experimental results of some embodiments of the present invention are shown in Table 3. Wherein, A represents IC ₅₀ values ≤5nM; B Representative IC ₅₀ value of 5 ~ 20nM; C Representative IC ₅₀ value of 300 ~ 600nM; D Representative IC ₅₀ values of> 600nM. [table 3] Example Compound PI3K IC ₅₀ (nM) α β γ Example 1 A D D Example 2 A D C Example 3 A / / Example 4 B D D Example 5 B / / Example 6 B / / Example 7 B / / Example 9 B / / Example 23 A / / Example 32 A C C Example 33 A D D Note: "/" means not tested.

It can be seen from Table 3 that the compound provided by the present invention has good PI3Kα kinase inhibitory activity, and has good PI3Kβ and PI3Kγ kinase subtype selectivity, which can avoid potential side effects caused by multi-target inhibition. [Example B: Cell Proliferation Test]

Method: CellTiter Glo assay was used to observe the growth inhibitory effects of some compounds of the present invention on human tumor cells MCF-7 and HGC27 cultured in vitro.

Detection method: Suspend MCF-7 cells in DMEM medium to form a cell suspension, adjust the cell concentration to 25000 cells/mL; suspend HGC27 cells in RPMI-1640 medium to form a cell suspension, adjust the cell concentration to 5000 cells/mL. Add 100 μL of cell suspension to a 96-well plate and place in a CO ₂ incubator overnight. The compound to be tested was dissolved in DMSO, and a 3-fold dilution was performed to obtain a total of 10 concentrations. Transfer 10 concentrations of the test compound or DMSO negative control substance to the wells containing 100 µL of culture medium, and culture at 37°C and 5% CO _2. HGC27 cells were cultured for 96 hours, and MCF-7 cells were cultured for 120 hours. Then add 100 μL CellTiter-Glo reagent to the above 96-well plate and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Use the VICTOR TM X5 instrument to record the RLU (relative luminescence unit) value, and then calculate the IC ₅₀ value. Compound inhibition rate (% inh)=100%-(compound to be tested RLU-blank control RLU)/(negative control RLU-blank control RLU)*100% Negative control: DMSO well; Blank control: blank medium well, none The compound is cell-free.

Use the following nonlinear fitting formula to obtain the IC ₅₀ (half inhibition concentration) of the compound: Y=minimum inhibition rate + (maximum inhibition rate-minimum inhibition rate)/(1+10^((LogIC ₅₀ -X)*slope) ); where X: the log value of the concentration of the compound to be tested; Y: the inhibition rate of the compound to be tested (% inh).

The experimental data are shown in Table 4 and Table 5. _{[Table 4 IC 50} test results of the compound of the embodiment on MCF cells] Example Compound against MCF cells IC ₅₀ (μM) Comparative example 1 0.444 Comparative example 2 0.549 Comparative example 3 0.519 Example 1 0.176 Example 2 0.070 Example 5 0.373 Example 9 0.142 Example 23 0.074 Example 28 0.468 Example 32 0.107 Example 33 0.047 _{[Table 5 IC 50} detection results of the compound of the embodiment on HGC-27 cells] Example Compound against HGC-27 cells IC ₅₀ (μM) Comparative example 1 1.579 Comparative example 3 2.067 Example 2 0.361 Example 5 4.071 Example 28 3.921 Example 32 0.415 Example 33 0.267

It can be seen from the above table that the compound provided by the present invention has better cell proliferation inhibitory activity for cell lines with PI3Kα point mutations than the control compound, and has a better anti-tumor effect at the same concentration. Therefore, the compound provided by the present invention is expected to become a PI3Kα kinase inhibitor with better anti-tumor effect. [Example C: Pharmacokinetic test]

Detection method: 42 male SD rats, weight: 150-300g. They were randomly divided into 7 groups, with 6 rats in each group. Among the 6 rats in each group, 3 rats were given a single intravenous injection of 2 mg/mL of the example compound, and the other 3 rats were given a single intravenous injection of 10 mg/mL of the example compound, and passed through the orbital venous plexus at designated time points. The blood was collected, the plasma was separated, and stored in the refrigerator at -80°C for later use.

After precipitating the protein with acetonitrile, the above-mentioned plasma sample was extracted and the supernatant was extracted and mixed with water 1:1, and 10 μL was taken to LC-MS/MS for detection, and the average value was calculated. The experimental data are shown in Table 6. [Table 6 Pharmacokinetic Test Results of Example Compounds] Compound number Intravenous injection Intragastric administration Dose (mg/kg) CL (mL/min/kg) Dose (mg/kg) C _max (ng/mL) AUC (hr*ng/mL) Comparative example 1 2 16.6 10 1963 7882 Example 2 2 1.98 10 4340 52993 Example 4 2 4.75 10 2690 29080 Example 23 2 8.76 10 1833 18563 Example 32 2 1.5 10 5033 66414 Example 33 2 11.1 10 1597 19832

According to relevant statistics (Kola I, Landis J. Nat Rev Drug Discov. 2004 Aug;3(8):711-5.), in the early 1990s, about 40% of drug candidates failed in clinical development due to PK/ The bioavailability is poor, which shows that PK/bioavailability plays a very critical role in the success or failure of the clinical development of candidate drugs.

It can be seen from the above table that the compound provided by the present invention has an unexpectedly higher oral exposure than the compound of the control example, and at the same time has a lower in vivo clearance rate; it can have a higher oral exposure rate at the same dose. The concentration of the drug in the circulatory system in the body. On the premise that the anti-tumor effect is equivalent, the administration dose of the compound of the present invention is lower, thereby reducing possible toxic reactions and safety risk probability, and effectively increasing the drugability of the compound.

without.

without.

without.

Claims (35)

A compound represented by formula (I) or its stereoisomers, geometric isomers or tautomers, or pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes or precursors thereof drug,

Formula (I) wherein X is selected from O or S; R _{1 is} selected from H, CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _6-8 aryl, C _5-8 heteroaryl, OR _a or -NR _a R _b ; the C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, C _6-8 aryl, and C _5-8 heteroaryl may optionally be selected from halogen, CN, OR _a , oxo group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl or C _3-6 heterocyclic group substituted ; R _{2 is} selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _6-8 aryl , C _5-8 heteroaryl; the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _{6 -8} aryl group and C _5-8 heteroaryl group can be optionally substituted by one or more selected from halogen, CN, -OH, -NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, C _3-6 heterocyclic group, C _3-6 halogenated heterocyclic group, C _6-8 aryl group, C _6-8 halogenated aryl group, C _5-8 heteroaryl group, C _5-8 halogenated heteroaryl group , Oxo group, -OR _a , -NR _a R _b , -C(O)R _a , -C(O)OR _a , -C(O)NR _a R _b , -S(O)R _{a or-} S(O) ₂ R _a is substituted by a substituent; R _{3 is} selected from H, halogen, CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OR _a or -NR _a R _b ; The C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group may optionally be selected from halogen, CN, -OR _a , -NR _a R _{b, -C (O) R a} , -C (O) oR a, -C (O) NR a R b, -S (O) R a , or -S (O) ₂ R _a the substituents; R _{4 is} selected from H, halogen, CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, oxo, C _1-6 haloalkyl, C _2-6 haloalkenyl , C _2-6 haloalkynyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -OR _a , -NR _a R _b , -C(O)R _a , -C(O)OR _{a, -C (O) NR a} R b, -S (O) R a , or _{-S (O) 2 R a;} R 5 is selected from H, halo, CN, C _1-6 alkyl, C _2-6 Alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _2-6 haloalkenyl, C _2-6 haloalkynyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -OR _a , -NR _a R _b , -S (O) R _a, or _{-S (O) 2 R a;} R 6 is selected from H, halogen, CN, oxo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _6-8 aryl, C _5-8 heteroaryl, -OR _a , -NR _a R _b , -C(O)R _a , -C(O)OR _a , -C(O) NR _a R _b , -S(O)R _a or -S(O) ₂ R _a ; the C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _6-8 aryl and C _{The 5-8} heteroaryl group can be optionally substituted by one or more selected from halogen, CN, oxo, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , -OR _a , -NR _a R _b , -C(O)R _a , -C(O)OR _a , -C(O)NR _a R _b , -S(O)R _a or -S(O) ₂ R _a group is substituted; or, two R ₆ and the C atom to which they are connected together form a C _3-6 cycloalkyl group or a C _3-6 heterocyclic group; R _a and R _b are each independently selected from H , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _6-8 Aryl, C _5-8 heteroaryl; the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _6-8 aryl, C _5-8 heteroaryl can be optionally substituted by halogen, CN, -OH, -NH ₂ , C _1-6 alkyl, C _1-6 alkane Substituted by oxy, C _1-6 haloalkyl, C _1-6 haloalkoxy; m is selected from 0, 1, 2, 3 or 4; n is selected from 0, 1, 2 or 3; y is selected from 0, 1 , 2, 3, 4, 5, or 6. The compound or its stereoisomers, geometric isomers or tautomers as described in claim 1, or its pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes or prodrugs , Wherein the R ₁ is a C _1-6 alkyl group or a C _3-6 cycloalkyl group, and the C _1-6 alkyl group and C _3-6 cycloalkyl group may be independently optionally substituted with halogen. The compound or its stereoisomer, geometric isomer or tautomer as described in claim 1 or 2, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or pro A drug, wherein the R _{2 is} selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C _6-8 aryl or C _5-8 heteroaryl ; The C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 heterocyclic group, C _6-8 aryl group and C _5-8 heteroaryl group may optionally be 1 or more _{halogen, -CN, -OH, -NR a R} b, C 1-6 alkyl or C _1-6 haloalkyl groups; said R _a and R _{b are} each independently selected from H or C _1-6 alkyl . The compound according to any one of claims 1 to 3 or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent A complex or prodrug, wherein the R _{3 is} selected from H, halogen, CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _2-6 haloalkenyl or C _2-6 haloalkynyl. The compound according to any one of claims 1 to 4 or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent A complex or prodrug, wherein the R _{6 is} selected from H, halogen, CN, -NH ₂ , oxo, -OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _2-6 haloalkenyl, C _2-6 haloalkynyl, C _3-6 cycloalkyl, C _3-6 heterocycle Group, C _6-8 aryl or C _5-8 heteroaryl. The compound according to any one of claims 1 to 5 or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent Complex or prodrug, wherein, further as shown in formula (II):

Formula (II). The compound according to any one of claims 1 to 6 or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent Complex or prodrug, wherein, further as shown in formula (Ⅲ-1):

Formula (III-1) wherein, R ₁ is a C _1-6 alkyl group or a C _1-6 haloalkyl group. The compound according to any one of claims 1 to 6 or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent Complex or prodrug, wherein, further as shown in formula (Ⅲ-2):

Formula (Ⅲ-2). The compound according to any one of claims 1 to 8 or its stereoisomers, geometric isomers and tautomers, or pharmaceutically acceptable salts, solvates, chelates, non-covalents thereof The complex or prodrug, wherein the R _{3 is} selected from H, halogen, C _1-6 alkyl or C _2-6 alkenyl. The compound according to any one of claims 1 to 9 or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent Complex or prodrug, wherein said R ₄ and R ₅ are both H. The compound according to any one of claims 1 to 6 or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent The complex or prodrug, wherein, further as shown in formula (IV):

Formula (IV) wherein: R ₁ is C _1-6 alkyl or C _1-6 haloalkyl; R _{2 is} selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocycle Group, C _6-8 aryl group or C _5-8 heteroaryl group; the C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 heterocyclic group, C _6-8 aryl group and C _{The 5-8} heteroaryl group can be optionally substituted by one or more halogen, -CN, -OH, -NR _a R _b , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy Group or C _1-6 haloalkoxy; R _{3 is} selected from H, halogen, C _1-6 alkyl or C _2-6 alkenyl; R _{6 is} selected from H, halogen, -NH ₂ , oxo , -OH, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl or C _6-8 aryl; R _a and R _b are each independently selected from H or C _1-6 alkyl; y is selected from 0, 1, 2, 3, 4, 5 or 6. The compound or its stereoisomers, geometric isomers or tautomers as described in claim 11, or its pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes or prodrugs , Wherein the X is O. The compound according to any one of claims 1 to 7 or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent Complex or prodrug, wherein, further as shown in formula (V):

式(V). The compound according to any one of claims 1 to 13 or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent The compound or prodrug, wherein the R _{2 is} selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C ₆ aryl or C _5-6 hetero Aryl; the C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 heterocyclic group, C ₆ aryl group and C _5-6 heteroaryl group may optionally be composed of 1 or more It is substituted by halogen, -CN, -OH, -N-(CH ₃ ) ₂ , C _1-6 alkyl or C _1-6 haloalkyl. The compound according to any one of claims 1 to 14 or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent A complex or prodrug, wherein the R _{6 is} selected from H, halogen, -NH ₂ , oxo, -OH, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 ring Alkyl or C ₆ aryl. The compound according to any one of claims 1 to 7 or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent Complex or prodrug, wherein, further as shown in formula (VI):

Formula (VI) wherein, R _{1 is} selected from C _1-6 alkyl or C _1-6 haloalkyl; R _{2 is} selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 hetero Cyclic group, C ₆ aryl group or C _5-6 heteroaryl group; the C _1-6 alkyl group, C _3-6 cycloalkyl group, C _3-6 heterocyclic group, C ₆ aryl group and C _5-6 Heteroaryl groups may be optionally substituted with one or more halogens, -CN, -OH, -N-(CH ₃ ) ₂ , C _1-6 alkyl, or C _1-6 haloalkyl. The compound according to any one of claims 1 to 16 or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent The complex or prodrug, wherein the R ₁ is a C _1-4 alkyl group, and the R _{1 is} optionally substituted with halogen. The compound according to any one of claims 1 to 17, or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent The complex or prodrug, wherein the R _{1 is} selected from -CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , -CF ₃ or -CHF ₂ . The compound according to any one of claims 1 to 18 or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent The compound or prodrug, wherein the R _{2 is} selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C ₆ aryl or C ₅ -C ₆ Heteroaryl, the R _{2 is} optionally substituted with halogen. The compound according to any one of claims 1 to 19 or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent The compound or prodrug, wherein the R _{2 is} selected from C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _3-6 halocycloalkyl, phenyl or Halophenyl. The compound according to any one of claims 1 to 7 or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent Complex or prodrug, wherein, further as shown in formula (VII):

Formula (VII) wherein, the R _{2 is} selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 heterocyclyl, C ₆ aryl or C _5-6 heteroaryl; The R _{2 is} optionally substituted with halogen. The compound according to any one of claims 1 to 21 or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent A complex or prodrug, wherein the R _{2 is} selected from -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CF ₃ , cyclopropyl, cyclobutyl, phenyl or Pyridyl; the -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CF ₃ , cyclopropyl, cyclobutyl, phenyl or pyridyl are optionally substituted with halogen. The compound according to any one of claims 1 to 22 or its stereoisomer, geometric isomer or tautomer, or its pharmaceutically acceptable salt, solvate, chelate, non-covalent The complex or prodrug, wherein the R _{2 is} selected from -CH ₃ , -CH(CH ₃ ) ₂ , cyclopropyl, phenyl, or halogen-substituted phenyl. The compound or its stereoisomers, geometric isomers or tautomers as described in claim 1, or its pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes or prodrugs , Wherein the compound or its stereoisomers, geometric isomers or tautomers are selected from: 1) (2S)-1-(2-(5-isopropyl-3-methyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole And [1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-methanamide; 2) (2S)-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f] Imidazole [1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-carboxamide; 3) (2S)-1-(2-(5-isopropyl-2,4-dioxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-yl)-5, 6-Dihydrobenzo[f]imidazole[1,2-d][1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 4) (2S)-1-(2-(3-(4-Fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzene And [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 5) (2S)-1-(2-(5-cyclopropyl-3-methyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole And [1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-methanamide; 6) (2S)-1-(2-(3-Cyclobutyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f] Imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 7) (2S)-1-(2-(3-Ethyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole And [1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-methanamide; 8) (2S)-1-(2-(5-Difluoromethyl-3-methyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f] Imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 9) (2S)-1-(2-(5-isopropyl-2,4-dioxo-3-phenylimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole And [1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-methanamide; 10) (S)-1-(2-((S)-5-isopropyl-2,4-dioxo-3-phenylimidazolidin-1-yl)-5,6-dihydrobenzo [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 11) (S)-1-(2-((R)-5-isopropyl-2,4-dioxo-3-phenylimidazolidin-1-yl)-5,6-dihydrobenzo [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 12) (2S)-1-(2-(5-isopropyl-2,4-dioxo-3-(4-(trifluoromethyl)phenyl)imidazolidine-1-yl)-5, 6-Dihydrobenzo[f]imidazole[1,2 -d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 13) (2S)-1-(2-(5-isopropyl-2,4-dioxo-3-propylimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole And [1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-methanamide; 14) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f ]Imidazo[1,2-d] [1,4]oxazepine-9-yl)-2-methylpyrrolidin-2-methamide; 15) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f ]Imidazo[1,2-d] [1,4]thiazolin-9-yl)-4,4-difluoropyrrolidine-2-methamide; 16) (2S)-1-(2-(5-isopropyl-3-(1-methyl-1H-1,2,4-triazol-5-yl)-2,4-dioxoimidazole Alkyl-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 17) (2S,4S)-4-amino-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-di Hydrobenzo[f]imidazole[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 18) (2S)-1-(2-(3-(2-Fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzene And [f]imidazole[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 19) (2S)-1-(2-(3-(4-chlorophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzene And [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 20) (2S)-4-(tert-butoxy)-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5, 6-Dihydrobenzo[f]imidazole[1,2] -d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 21) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f ]Imidazo[1,2-d] [1,4]oxazepine-9-yl)-4,4-dimethylpyrrolidine-2-methamide; 22) (2S)-1-(2-(3-(2,2-Difluoroethyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6- Dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 23) (2S)-1-(2-(3,5-Diisopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f]imidazo[ 1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-carboxamide; 24) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f ]Imidazo[1,2-d] [1,4]oxazepine-9-yl)-4-phenylpyrrolidine-2-methamide; 25) (2S)-1-(2-(3-(3-chloro5-cyanophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6 -Dihydrobenzo[f]imidazo[1,2 -d] [1,4]thiazolin-9-yl)pyrrolidine-2-carboxamide; 26) (2S)-1-(2-(3,5-Diisopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f]imidazo[ 1,2-d] [1,4]thiazolin-9-yl)pyrrolidine-2-carboxamide; 27) (2S)-1-(2- (3-azetidin-3-yl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6- Dihydrobenzo[f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 28) (2S)-1-(2-(3-Methyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2- d] [1,4] oxazepine-9-yl)pyrrolidine-2-carboxamide; 29) (2S)-1-(2- (5-tert-butyl-3-methyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole And [1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-carboxamide; 30) (S)-1-(2-((R)-3-(4-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6 -Dihydrobenzo[f]imidazo[1,2]-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 31) (S)-1-(2-((S)-3-(4-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6 -Dihydrobenzo[f]imidazo[1,2] -d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 32) (2S)-1-(2-((5R)-3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzene And [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 33) (2S)-1-(2-((5S)-3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzene And [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 34) (2S)-1-(2-(3-(2-hydroxyethyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzene And [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 35) (2S)-1-(2-(3-(2-Fluoroethyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzene And [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 36) (2S)-1-(2-(3-(2-(dimethylamino)ethyl)-5-)isopropyl-2,4-dioxoimidazolidine-1-yl)-5 ,6-Dihydrobenzo[f]imidazo[1,2- d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 37) (2S)-1-(2-(3-cyclopropyl-5-isopropyl)-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f ]Imidazo[1,2-d] [1,4]thiazolin-9-yl)pyrrolidine-2-carboxamide; 38) (2S)-1-(2-(3-(6-Fluoropyridin-3-yl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6- Dihydrobenzo[f]imidazo[1,2 -d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 39) (2S)-1-(2-(3-(5-fluoropyridin-3-yl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-di Hydrobenzo[f]imidazo[1,2] -d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 40) (2S)-1-(2-(3-(3-cyano-5-fluorophenyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5, 6-Dihydrobenzo[f]imidazo[1,2 -d] [1,4]oxazepine-9-yl)-4-fluoropyrrolidine-2-methamide; 41) (2S)-1-(2-(3-(3-Chloropyrimidin-2-yl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6- Dihydrobenzo[f]imidazo[1,2 -d] [1,4]oxazepine-9-yl)pyrrolidine-2-methanamide; 42) (2S)-1-(2-(3-cyclopentyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f] Imidazole [1,2-d] [1,4] oxazepine-9-yl)pyrrolidine-2-carboxamide; 43) (2S)-1-(2-(3-(cyanomethyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 44) (2S)-1-(2-(5-isopropyl-3-methyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo(f)imidazole And [1,2-d] [1,4]thiazolin-9-yl)pyrrolidine-2-methamide; 45) (2S)-1-(2-(3-(2,2-Difluoroethyl)-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6- Dihydrobenzo[f]imidazo[1,2-d] [1,4]thiazolin-9-yl)pyrrolidine-2-carboxamide; 46) (2S)-1-(2-(3-Cyclopropyl-5-isopropyl-2,4-dioxoimidazolidin-1-yl)-3-vinyl-5,6-dihydro Benzo[f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 47) (2S)-1-(3-Chloro-2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzene And [f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 48) (2S)-1-(2-(3-Cyclopropyl-5-(difluoromethyl)-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo [f]imidazo[1,2-d] [1, 4]thiazolin-9-yl)pyrrolidine-2-carboxamide; 49) (2S,3S)-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[ f]imidazo[1,2-d][1,4]oxazepine-9-yl)-3-hydroxypyrrolidine-2-methamide; 50) (2S)-1-(2-(3-Cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-3-methyl-5,6-dihydro Benzo[f]imidazo[1,2-d] [1,4]oxazepine-9-yl)-4-oxopyrrolidine-2-methamide; 51) (2S)-4-cyclohexyl-1-(2-(3-cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydro Benzo[f]imidazo[1,2-d] [1,4]oxazepine-9-yl)pyrrolidine-2-methamide; 52) (2S)-1-(2-(3-Cyclopropyl-5-isopropyl-2,4-dioxoimidazolidine-1-yl)-5,6-dihydrobenzo[f] Imidazo[1,2-d] [1,4]thiazolin-9-yl)-5-oxopyrrolidine-2-carboxamide. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any one of claims 1 to 24 or its stereoisomers, geometric isomers or tautomers, or a pharmaceutically acceptable salt thereof , Solvate, chelate, non-covalent complex or prodrug; and at least one pharmaceutically acceptable excipient. The pharmaceutical composition according to claim 25, wherein the compound or its stereoisomers, geometric isomers or tautomers, or pharmaceutically acceptable salts, solvates, chelates, non- The weight ratio of the covalent complex or prodrug and the pharmaceutically acceptable excipient is 0.0001-10. A compound according to any one of claims 1 to 24, or a stereoisomer, geometric isomer, or tautomer, or a pharmaceutically acceptable salt, solvate, chelate, or non-covalent The application of the compound or prodrug or the pharmaceutical composition described in claim 25 or 26 in the preparation of medicines. The use according to claim 27, wherein the medicament is used to treat, prevent, delay or prevent the occurrence or progression of cancer or cancer metastasis. The use according to claim 28, wherein the drug is used as a PI3K inhibitor. The use according to claim 27, wherein the drug is used to treat PI3K-mediated diseases. The application according to claim 29 or 30, wherein the PI3K is PI3Kα, PI3Kβ, PI3Kδ, and/or PI3Kγ. The application according to claim 31, wherein the PI3K is PI3Kα. The application according to claim 30, wherein the PI3K-mediated disease is cancer. The use according to claim 33, wherein the cancer is selected from the group consisting of sarcoma, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colorectal cancer, thyroid cancer, liver cancer, adrenal cancer, glioma, and endometrial cancer , Melanoma, kidney cancer, bladder cancer, uterine cancer, vagina cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, brain cancer, oral and pharynx cancer, laryngeal cancer, lymphoma, basal cell carcinoma, polycythemia vera Disease, essential thrombocytosis. The application according to claim 34, wherein the treatment target of the cancer is a human.